Histone demethylase inhibitors

ABSTRACT

The present invention relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted amidopyridine or amidopyridazine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

RELATED APPLICATIONS

This Application is a continuation of U.S. patent application Ser. No.15/636,420, filed Jun. 28, 2017, which is a continuation of U.S. patentapplication Ser. No. 15/441,142 (now U.S. Pat. No. 9,725,441), filedFeb. 23, 2017, which is a continuation of U.S. patent application Ser.No. 15/236,142, filed Aug. 12, 2016 (now U.S. Pat. No. 9,611,221), whichis a continuation of U.S. patent application Ser. No. 14/740,143, filedJun. 15, 2015 (now U.S. Pat. No. 9,447,045), which is a continuation ofU.S. patent application Ser. No. 14/592,830, filed Jan. 8, 2015 (nowU.S. Pat. No. 9,085,534), which is a division of U.S. patent applicationSer. No. 14/139,197, filed Dec. 23, 2013 (now U.S. Pat. No. 8,952,151),which claims priority benefit of U.S. Provisional Patent ApplicationsNo. 61/785,380, filed Mar. 14, 2013, and No. 61/745,246, filed Dec. 21,2012, the contents of which are hereby incorporated by reference intheir entireties for all purposes.

BACKGROUND

A need exists in the art for an effective treatment of cancer andneoplastic disease.

SUMMARY OF THE INVENTION

Provided herein are substituted pyridine and pyridazine derivativecompounds and pharmaceutical compositions comprising said compounds. Thesubject compounds and compositions are useful for inhibition of histonedemethylase. Furthermore, the subject compounds and compositions areuseful for the treatment of cancer, such as prostate cancer, breastcancer, bladder cancer, lung cancer and/or melanoma and the like. Thesubstituted pyridine and pyridazine derivative compounds describedherein are based upon a disubstituted pyridine or pyridazine ringbearing at the 4-position a carboxylic acid, a carboxylic acid ester, ora carboxylic acid bioisostere thereof, and at the 3-position asubstituted amino group.

One embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof,

-   -   wherein:    -   Q is —CO₂R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   R is hydrogen or optionally substituted alkyl;    -   G is —X—Y;        -   X is —C₁ alkylene;        -   Y is optionally substituted tetralinyl, optionally            substituted tetrahydroquinolinyl, substituted pyridyl,            optionally substituted naphthyl, optionally substituted            indolyl, optionally substituted benzofuranyl, optionally            substituted adamantyl, or optionally substituted indanyl.

One embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof,

-   -   wherein:    -   Q is —CO₂R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   R is hydrogen or optionally substituted alkyl;    -   G is —X—Y;        -   X is —C₁ alkylene;        -   Y is phenyl substituted with alkenyl, alkynyl, fluoro,            chloro, fluoroalkyl, nitro, optionally substituted aralkyl,            optionally substituted aralkenyl, optionally substituted            aralkynyl, optionally substituted carbocyclyl, optionally            substituted carbocyclylalkyl, optionally substituted            heterocyclyl, optionally substituted heterocyclylalkyl,            optionally substituted heteroaryl, optionally substituted            heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),            —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,            —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),            —R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),            —R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a),            —R^(b)—S(O)_(t)OR^(a), —R^(b)—S(O)_(t)OR^(a), and            —R^(b)—S(O)_(t)N(R^(a))₂;            -   wherein:                -   each R^(a) is independently hydrogen, alkyl,                    fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl,                    aralkyl, heterocyclyl, heterocyclylalkyl,                    heteroaryl, or heteroarylalkyl;                -   each R^(b) is independently a direct bond or a                    straight or branched alkylene or alkenylene chain;                -   each R^(c) is a straight or branched alkylene or                    alkenylene chain; and                -   t is 1 or 2.

One embodiment provides a compound of Formula (XV), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   Q is —CO₂R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   R is hydrogen or optionally substituted alkyl;    -   G is —X—Y;        -   X is —C₁ alkylene;        -   Y is carbocyclyl, heterocyclyl, aryl, or heteroaryl;    -   with the provisio that G is not

One embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof,

-   -   wherein:    -   Q is —CO₂R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   R is hydrogen or optionally substituted alkyl;    -   G is —X—Y;        -   X is —C₁ alkylene;        -   Y is optionally substituted tetralinyl, optionally            substituted chromanyl, optionally substituted            tetrahydroquinolinyl, optionally substituted benzofuranyl,            optionally substituted 2,3-dihydrobenzofuranyl, optionally            substituted 2,3-dihydrobenzo[b][1,4]dioxinyl, optionally            substituted naphthyl, optionally substituted indolyl,            optionally substituted 1,2-dihydronaphthyl, optionally            substituted indanyl, or optionally substituted            thiochromanyl.

Another embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein the compound ofFormula (XI) has the structure of Formula (XIa):

-   -   wherein,        -   R¹ is hydrogen, methyl, or —OH;        -   each R⁴ is independently hydrogen, fluoro, or methyl; and        -   R⁵, R⁶, R⁷ and R⁸ are each independently chosen from            hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆            alkyl, optionally substituted C₁-C₆ alkoxy, optionally            substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇            carbocyclyloxy, optionally substituted C₄-C₁₂            carbocyclylalkyl, optionally substituted C₄-C₁₂            carbocyclylalkoxy, optionally substituted C₁-C₆ alkynyl,            optionally substituted C₁-C₆ alkenyl, optionally substituted            C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,            optionally substituted C₆-C₁₀ aryl-S—, optionally            substituted C₇-C₁₄ aralkoxy, optionally substituted            heteroaryl, and optionally substituted heteroaryloxy.

Another embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein the compound ofFormula (XI) has the structure of Formula (XIb):

-   -   wherein,        -   R¹ is hydrogen, methyl, or —OH; and        -   R⁵, R⁶, R⁷ and R⁸ are each independently chosen from            hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆            alkyl, optionally substituted C₁-C₆ alkoxy, optionally            substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇            carbocyclyloxy, optionally substituted C₄-C₁₂            carbocyclylalkyl, optionally substituted C₄-C₁₂            carbocyclylalkoxy, optionally substituted C₁-C₆ alkynyl,            optionally substituted C₁-C₆ alkenyl, optionally substituted            C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,            optionally substituted C₆-C₁₀ aryl-S—, optionally            substituted C₇-C₁₄ aralkoxy, optionally substituted            heteroaryl, and optionally substituted heteroaryloxy.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises two to ten carbon atoms (e.g., C₂-C₁₀alkyl). In other embodiments, an alkyl comprises three to five carbonatoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group isselected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl),2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl(n-pentyl). The alkyl is attached to the rest of the molecule by asingle bond. Unless stated otherwise specifically in the specification,an alkyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds.) A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. The heteroatoms in theheterocyclyl radical may be optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl may be attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxo-piperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxa-zolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo-[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]-thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexa-hydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexa-hydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydro-quinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octa-hydrobenzo[h]quinazolinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyrazolo[3,4-d]-pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, 5,6,7,8-tetrahydro-quinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5Hcyclo-hepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]-pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]-pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.,thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

The compounds, or their pharmaceutically acceptable salts, in someinstances, contain one or more asymmetric centers and thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that aredefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers (e.g., cis or trans). Likewise,all possible isomers, as well as their racemic and optically pure forms,and all tautomeric forms are also intended to be included. The term“geometric isomer” refers to E or Z geometric isomers (e.g., cis ortrans) of an alkene double bond. The term “positional isomer” refers tostructural isomers around a central ring, such as ortho-, meta-, andpara-isomers around a benzene ring.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. It is contemplated that the disclosureprovided herein encompasses the various stereoisomers and mixturesthereof and includes “enantiomers,” which refers to two stereoisomerswhose molecular structures are nonsuperimposeable mirror images of oneanother.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedamidopyridine or amidopyridazine derivative compounds described hereinis intended to encompass any and all pharmaceutically suitable saltforms. Preferred pharmaceutically acceptable salts of the compoundsdescribed herein are pharmaceutically acceptable acid addition salts andpharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitro-benzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, e.g.,Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 66:1-19 (1997), whichis hereby incorporated by reference in its entirety). Acid additionsalts of basic compounds may be prepared by contacting the free baseforms with a sufficient amount of the desired acid to produce the saltaccording to methods and techniques with which a skilled artisan isfamiliar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi et al., Pro-drugs asNovel Delivery Systems, A.C.S. Symposium Series, Vol. 14; and inBIOREVERSIBLE CARRIERS IN DRUG DESIGN, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

Substituted Pyridine or Pyridazine Derivative Compounds

Substituted pyridine and pyridazine derivative compounds are describedherein that inhibit a histone demethylase enzyme. These compounds, andcompositions comprising these compounds, are useful for the treatment ofcancer and neoplastic disease. The compounds described herein may,therefore, be useful for treating prostate cancer, breast cancer,bladder cancer, lung cancer and/or melanoma and the like.

One embodiment provides a compound of Formula (I), or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   -   wherein,    -   R is hydrogen or alkyl;    -   G is —X—Y;        -   X is —C₁-C₅ alkylene, —(C₁-C₅ alkylene)-Z—(C₁-C₅ alkylene)-,            or —(C₁-C₅ alkylene)-Z—;        -   Y is carbocyclyl, heterocyclyl, aryl, or heteroaryl; and            -   Z is

and n is 0, 1, 2, or 3;

-   -   with the provision: G is not

Another embodiment provides the compound of Formula (I), wherein X is aC₁ alkylene. Another embodiment provides the compound of Formula (I),wherein X is a C₂ alkylene. Another embodiment provides the compound ofFormula (I), wherein X is a C₃ alkylene. Another embodiment provides thecompound of Formula (I), wherein X is —(C₁-C₅ alkylene)-Z—. Anotherembodiment provides the compound of Formula (I), wherein X is —(C₁alkylene)-Z—. Another embodiment provides the compound of Formula (I),wherein X is —(C₁ alkylene)-Z—, and n is 0, 1 or 2. Another embodimentprovides the compound of Formula (I), wherein Y is carbocyclyl. Anotherembodiment provides the compound of Formula (I), wherein Y isheterocyclyl. Another embodiment provides the compound of Formula (I),wherein Y is aryl. Another embodiment provides the compound of Formula(I), wherein Y is heteroaryl. Another embodiment provides the compoundof Formula (I), wherein R¹ is hydrogen. Another embodiment provides thecompound of Formula (I), wherein R¹ is alkyl.

One embodiment provides a compound of Formula (III), or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   -   wherein,    -   R is hydrogen or alkyl;    -   G is —X—Y;        -   X is —C₁-C₅ alkylene, —(C₁-C₅ alkylene)-Z—(C₁-C₅ alkylene)-,            or —(C₁-C₅ alkylene)-Z—;        -   Y is carbocyclyl, or heterocyclyl; and            -   Z is

and n is 0, 1, 2, or 3.

Another embodiment provides the compound of Formula (III), wherein X isa C1 alkylene. Another embodiment provides the compound of Formula(III), wherein X is a C₂ alkylene. Another embodiment provides thecompound of Formula (III), wherein X is a C₃ alkylene. Anotherembodiment provides the compound of Formula (III), wherein X is —(C₁-C₅alkylene)-Z—. Another embodiment provides the compound of Formula (III),wherein X is —(C₁ alkylene)-Z—. Another embodiment provides the compoundof Formula (III), wherein X is —(C₁ alkylene)-Z—, and n is 0, 1 or 2.Another embodiment provides the compound of Formula (III), wherein Y iscarbocyclyl. Another embodiment provides the compound of Formula (III),wherein Y is heterocyclyl. Another embodiment provides the compound ofFormula (III), wherein R¹ is hydrogen. Another embodiment provides thecompound of Formula (III), wherein R¹ is alkyl.

One embodiment provides a compound of Formula (V), or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   -   wherein,    -   R is hydrogen or alkyl;    -   G is R¹ or R²;        -   R¹ is —CO—R³, —CO₂—R³ or —CO—N(R⁴)₂;            -   R³ is alkyl;            -   R⁴ is H or alkyl, wherein, optionally, if both R⁴ groups                are alkyl, then they may, together with the nitrogen to                which they are attached, join to form a ring;        -   R² is —X—Y;            -   X is —C₁-C₅ alkylene, —CO—C₁-C₅ alkylene, —(C₁-C₅                alkylene)-Z—, —(C₁-C₅ alkylene)-Z—(C₁-C₅ alkylene)-,                —CO—(C₁-C₅ alkylene)-Z—, —CO—(C₁-C₅ alkylene)-Z—(C₁-C₅                alkylene)-, or —C(═N—Oalkyl)-;            -   Y is carbocyclyl, heterocyclyl, aryl, or heteroaryl;            -   Z is

and n is 0, 1, 2, or 3;

-   -   with the provision: G is not

Another embodiment provides the compound of Formula (V), wherein G isR¹. Another embodiment provides the compound of Formula (V), wherein Gis R².

One embodiment provides a compound of Formula (XI), or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   -   wherein,    -   Q is —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   G is —X—Y;        -   X is —C₁-C₅ alkylene, —(C₁-C₅ alkylene)-Z—(C₁-C₅ alkylene)-,            or —(C₁-C₅ alkylene)-Z—;        -   Y is carbocyclyl, heterocyclyl, aryl, or heteroaryl; and            -   Z is

and n is 0, 1, 2, or 3.

Another embodiment provides the compound of Formula (XI) wherein G isnot

Another embodiment provides the compound of Formula (XI), wherein X is aC₁ alkylene. Another embodiment provides the compound of Formula (XI),wherein X is a C₂ alkylene. Another embodiment provides the compound ofFormula (XI), wherein X is a C₃ alkylene. Another embodiment providesthe compound of Formula (XI), wherein X is —(C₁-C₅ alkylene)-Z—. Anotherembodiment provides the compound of Formula (XI), wherein X is —(C₁alkylene)-Z—. Another embodiment provides the compound of Formula (XI),wherein X is —(C₁ alkylene)-Z—, and n is 0, 1 or 2. Another embodimentprovides the compound of Formula (XI), wherein Y is carbocyclyl. Anotherembodiment provides the compound of Formula (XI), wherein Y isheterocyclyl. Another embodiment provides the compound of Formula (XI),wherein Y is aryl. Another embodiment provides the compound of Formula(XI), wherein Y is heteroaryl. Another embodiment provides the compoundof Formula (XI), wherein Q is tetrazolyl. Another embodiment providesthe compound of Formula (XI), wherein Q is —C(O)N(H)CN. Anotherembodiment provides the compound of Formula (XI), wherein Q is—C(O)N(H)OH.

One embodiment provides a compound of Formula (XIII), or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   -   wherein,    -   Q is —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   G is —X—Y;        -   X is —C₁-C₅ alkylene, —(C₁-C₅ alkylene)-Z—(C₁-C₅ alkylene)-,            or —(C₁-C₅ alkylene)-Z—;        -   Y is carbocyclyl, or heterocyclyl; and            -   Z is

and n is 0, 1, 2, or 3.

Another embodiment provides the compound of Formula (XIII), wherein X isa C1 alkylene. Another embodiment provides the compound of Formula(XIII), wherein X is a C2 alkylene. Another embodiment provides thecompound of Formula (XIII), wherein X is a C3 alkylene. Anotherembodiment provides the compound of Formula (XIII), wherein X is —(C₁-C₅alkylene)-Z—. Another embodiment provides the compound of Formula(XIII), wherein X is —(C₁ alkylene)-Z—. Another embodiment provides thecompound of Formula (XIII), wherein X is —(C₁ alkylene)-Z—, and n is 0,1 or 2. Another embodiment provides the compound of Formula (XIII),wherein Y is carbocyclyl. Another embodiment provides the compound ofFormula (XIII), wherein Y is heterocyclyl. Another embodiment providesthe compound of Formula (XIII), wherein Q is tetrazolyl. Anotherembodiment provides the compound of Formula (XIII), wherein Q is—C(O)N(H)CN. Another embodiment provides the compound of Formula (XIII),wherein Q is —C(O)N(H)OH.

One embodiment provides a compound of Formula (XV), or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   -   wherein,    -   Q is —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   G is R¹ or R²;        -   R¹ is —CO—R³, —CO₂—R³ or —CO—N(R⁴)₂;            -   R³ is alkyl;            -   R⁴ is H or alkyl, wherein, optionally, if both R⁴ groups                are alkyl, then they may, together with the nitrogen to                which they are attached, join to form a ring;        -   R² is —X—Y;            -   X is —C₁-C₅ alkylene, —CO—C₁-C₅ alkylene, —(C₁-C₅                alkylene)-Z—, —(C₁-C₅ alkylene)-Z—(C₁-C₅ alkylene)-,                —CO—(C₁-C₅ alkylene)-Z—, —CO—(C₁-C₅ alkylene)-Z—(C₁-C₅                alkylene)-, or —C(═N—Oalkyl)-;            -   Y is carbocyclyl, heterocyclyl, aryl, or heteroaryl; and                -   Z is

and n is 0, 1, 2, or 3.

Another embodiment provides the compound of Formula (XV), wherein G isnot

Another embodiment provides the compound of Formula (XV), wherein G isR¹. Another embodiment provides the compound of Formula (XV), wherein Gis R². Another embodiment provides the compound of Formula (XV), whereinQ is tetrazolyl. Another embodiment provides the compound of Formula(XV), wherein Q is —C(O)N(H)CN. Another embodiment provides the compoundof Formula (XV), wherein Q is —C(O)N(H)OH.

One embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof,

-   -   wherein:    -   Q is —CO₂R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   R is hydrogen or optionally substituted alkyl;    -   G is —X—Y;        -   X is —C₁ alkylene;        -   Y is optionally substituted tetralinyl, optionally            substituted tetrahydroquinolinyl, substituted pyridyl,            optionally substituted naphthyl, optionally substituted            indolyl, optionally substituted benzofuranyl, optionally            substituted adamantyl, or optionally substituted indanyl.

One embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof,

-   -   wherein:    -   Q is —CO₂R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   R is hydrogen or optionally substituted alkyl;    -   G is —X—Y;        -   X is —C₁ alkylene;        -   Y is phenyl substituted with alkenyl, alkynyl, fluoro,            chloro, fluoroalkyl, nitro, optionally substituted aralkyl,            optionally substituted aralkenyl, optionally substituted            aralkynyl, optionally substituted carbocyclyl, optionally            substituted carbocyclylalkyl, optionally substituted            heterocyclyl, optionally substituted heterocyclylalkyl,            optionally substituted heteroaryl, optionally substituted            heteroarylalkyl, R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),            —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,            —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),            —R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),            —R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a),            —R^(b)—S(O)_(t)OR^(a), —R^(b)—S(O)_(t)OR^(a), and            —R^(b)—S(O)_(t)N(R^(a))₂;            -   wherein:                -   each R^(a) is independently hydrogen, alkyl,                    fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl,                    aralkyl, heterocyclyl, heterocyclylalkyl,                    heteroaryl, or heteroarylalkyl;                -   each R^(b) is independently a direct bond or a                    straight or branched alkylene or alkenylene chain;                -   each R^(c) is a straight or branched alkylene or                    alkenylene chain; and                -   t is 1 or 2.

One embodiment provides a compound of Formula (XV), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   Q is —CO₂R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   R is hydrogen or optionally substituted alkyl;    -   G is —X—Y;        -   X is —C₁ alkylene;        -   Y is carbocyclyl, heterocyclyl, aryl, or heteroaryl;        -   with the provisio that G is not

Another embodiment provides the compound or pharmaceutically acceptablesalt of Formula (XI) or Formula (XV), wherein Q is —CO₂R. Anotherembodiment provides the compound or pharmaceutically acceptable salt ofFormula (XI) or Formula (XV), wherein Q is —C(O)N(H)CN. Anotherembodiment provides the compound or pharmaceutically acceptable salt ofFormula (XI) or Formula (XV), wherein Q is —C(O)N(H)OH. Anotherembodiment provides the compound or pharmaceutically acceptable salt ofFormula (XI) or Formula (XV), wherein Q is tetrazolyl. Anotherembodiment provides the compound or pharmaceutically acceptable salt ofFormula (XI) or Formula (XV), wherein R is hydrogen. Another embodimentprovides the compound or pharmaceutically acceptable salt of Formula(XI) or Formula (XV), wherein R is optionally substituted alkyl. Anotherembodiment provides the compound or pharmaceutically acceptable salt ofFormula (XI) or Formula (XV), wherein Y is optionally substitutedtetralinyl. Another embodiment provides the compound or pharmaceuticallyacceptable salt of Formula (XI) or Formula (XV), wherein Y is optionallysubstituted tetrahydroquinolinyl. Another embodiment provides thecompound or pharmaceutically acceptable salt of Formula (XI) or Formula(XV), wherein Y is substituted pyridyl. Another embodiment provides thecompound or pharmaceutically acceptable salt of Formula (XI) or Formula(XV), wherein Y is optionally substituted naphthyl. Another embodimentprovides the compound or pharmaceutically acceptable salt of Formula(XI) or Formula (XV), wherein Y is optionally substituted indolyl.Another embodiment provides the compound or pharmaceutically acceptablesalt of Formula (XI) or Formula (XV), wherein Y is optionallysubstituted benzofuranyl. Another embodiment provides the compound orpharmaceutically acceptable salt of Formula (XI) or Formula (XV),wherein Y is optionally substituted adamantyl. Another embodimentprovides the compound or pharmaceutically acceptable salt of Formula(XI) or Formula (XV), wherein Y is optionally substituted indanyl.

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, selected from the group consisting of:

One embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof,

-   -   wherein:    -   Q is —CO₂R, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;    -   R is hydrogen or optionally substituted alkyl;    -   G is —X—Y;        -   X is —C₁ alkylene;        -   Y is optionally substituted tetralinyl, optionally            substituted chromanyl, optionally substituted            tetrahydroquinolinyl, optionally substituted benzofuranyl,            optionally substituted 2,3-dihydrobenzofuranyl, optionally            substituted 2,3-dihydrobenzo[b]-[1,4]dioxinyl, optionally            substituted naphthyl, optionally substituted indolyl,            optionally substituted 1,2-dihydronaphthyl, optionally            substituted indanyl, or optionally substituted            thiochromanyl.

Another embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein Q is —CO₂R. Anotherembodiment provides a compound of Formula (XI), or a pharmaceuticallyacceptable salt thereof, wherein Q is —C(O)N(H)CN. Another embodimentprovides a compound of Formula (XI), or a pharmaceutically acceptablesalt thereof, wherein Q is —C(O)N(H)OH. Another embodiment provides acompound of Formula (XI), or a pharmaceutically acceptable salt thereof,wherein Q is tetrazolyl. Another embodiment provides a compound ofFormula (XI), or a pharmaceutically acceptable salt thereof, wherein Ris hydrogen. Another embodiment provides a compound of Formula (XI), ora pharmaceutically acceptable salt thereof, wherein R is optionallysubstituted alkyl. Another embodiment provides a compound of Formula(XI), or a pharmaceutically acceptable salt thereof, wherein Y isoptionally substituted chromanyl. Another embodiment provides a compoundof Formula (XI), or a pharmaceutically acceptable salt thereof, whereinY is optionally substituted tetrahydroquinolinyl. Another embodimentprovides a compound of Formula (XI), or a pharmaceutically acceptablesalt thereof, wherein Y is optionally substituted benzofuranyl. Anotherembodiment provides a compound of Formula (XI), or a pharmaceuticallyacceptable salt thereof, wherein Y is optionally substituted2,3-dihydrobenzofuranyl. Another embodiment provides a compound ofFormula (XI), or a pharmaceutically acceptable salt thereof, wherein Yis optionally substituted naphthyl. Another embodiment provides acompound of Formula (XI), or a pharmaceutically acceptable salt thereof,wherein Y is optionally substituted indolyl. Another embodiment providesa compound of Formula (XI), or a pharmaceutically acceptable saltthereof, wherein Y is optionally substituted 1,2-dihydronaphthyl.Another embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein Y is optionallysubstituted indanyl. Another embodiment provides a compound of Formula(XI), or a pharmaceutically acceptable salt thereof, wherein Y isoptionally substituted thiochromanyl. Another embodiment provides acompound of Formula (XI), or a pharmaceutically acceptable salt thereof,wherein Y is optionally substituted tetralinyl. Another embodimentprovides a compound of Formula (XI), or a pharmaceutically acceptablesalt thereof, wherein the optionally substituted tetralinyl is anoptionally substituted 1-tetralinyl.

Another embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein the compound ofFormula (XI) has the structure of Formula (XIa):

-   -   wherein,        -   R¹ is hydrogen, methyl, or —OH;        -   each R⁴ is independently hydrogen, fluoro, or methyl; and        -   R⁵, R⁶, R⁷ and R⁸ are each independently chosen from            hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆            alkyl, optionally substituted C₁-C₆ alkoxy, optionally            substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇            carbocyclyloxy, optionally substituted C₄-C₁₂            carbocyclylalkyl, optionally substituted C₄-C₁₂            carbocyclylalkoxy, optionally substituted C₁-C₆ alkynyl,            optionally substituted C₁-C₆ alkenyl, optionally substituted            C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,            optionally substituted C₆-C₁₀ aryl-S—, optionally            substituted C₇-C₁₄ aralkoxy, optionally substituted            heteroaryl, and optionally substituted heteroaryloxy.

Another embodiment provides a compound of Formula (XIa), wherein each R⁴is hydrogen. Another embodiment provides a compound of Formula (XIa),wherein each R⁴ is fluoro. Another embodiment provides a compound ofFormula (XIa), wherein each R⁴ is methyl. Another embodiment provides acompound of Formula (XIa), wherein one R⁴ is hydrogen. Anotherembodiment provides a compound of Formula (XIa), wherein one R⁴ isfluoro.

Another embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein Y is optionallysubstituted chromanyl. Another embodiment provides a compound of Formula(XI), or a pharmaceutically acceptable salt thereof, wherein theoptionally substituted chromanyl is an optionally substituted4-chromanyl.

Another embodiment provides a compound of Formula (XI), or apharmaceutically acceptable salt thereof, wherein the compound ofFormula (XI) has the structure of Formula (XIb):

-   -   wherein,        -   R¹ is hydrogen, methyl, or —OH; and        -   R⁵, R⁶, R⁷ and R⁸ are each independently chosen from            hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆            alkyl, optionally substituted C₁-C₆ alkoxy, optionally            substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇            carbocyclyloxy, optionally substituted C₄-C₁₂            carbocyclylalkyl, optionally substituted C₄-C₁₂            carbocyclylalkoxy, optionally substituted C₁-C₆ alkynyl,            optionally substituted C₁-C₆ alkenyl, optionally substituted            C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,            optionally substituted C₆-C₁₀ aryl-S—, optionally            substituted C₇-C₁₄ aralkoxy, optionally substituted            heteroaryl, and optionally substituted heteroaryloxy.

Another embodiment provides a compound of Formula (XIa) or (XIb), or apharmaceutically acceptable salt thereof, wherein R¹ is hydrogen.Another embodiment provides a compound of Formula (XIa) or (XIb),wherein R⁵ is hydrogen. Another embodiment provides a compound ofFormula (XIa) or (XIb), wherein R⁶ is hydrogen. Another embodimentprovides a compound of Formula (XIa) or (XIb), wherein R⁷ is hydrogen.Another embodiment provides a compound of Formula (XIa) or (XIb),wherein R⁸ is hydrogen. Another embodiment provides a compound ofFormula (XIa) or (XIb), wherein R⁵ and R⁷ are hydrogen. Anotherembodiment provides a compound of Formula (XIa) or (XIb), wherein R⁵ andR⁸ are hydrogen. Another embodiment provides a compound of Formula (XIa)or (XIb), wherein R⁷ and R⁸ are hydrogen. Another embodiment provides acompound of Formula (XIa) or (XIb), wherein R⁶ is not hydrogen.

Another embodiment provides a compound of Formula (XIa) or (XIb),wherein R⁶ is chosen from optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ alkoxy, optionally substituted C₃-C₇ carbocyclyl,optionally substituted C₃-C₇ carbocyclyloxy, optionally substitutedC₄-C₁₂ carbocyclylalkyl, optionally substituted C₄-C₁₂carbocyclylalkoxy, optionally substituted C₁-C₆ alkynyl, optionallysubstituted C₁-C₆ alkenyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₆-C₁₀ aryloxy, optionally substituted C₆-C₁₀aryl-S—, optionally substituted C₇-C₁₄ aralkoxy, optionally substitutedheteroaryl, and optionally substituted heteroaryloxy.

Another embodiment provides a compound of Formula (XIa) or (XIb),wherein R⁶ is chosen from optionally substituted C₁-C₆ alkyl. Anotherembodiment provides a compound of Formula (XIa) or (XIb), wherein R⁶ ischosen from optionally substituted C₁-C₆ alkoxy. Another embodimentprovides a compound of Formula (XIa) or (XIb), wherein R⁶ is chosen fromoptionally substituted C₃-C₇ carbocyclyl. Another embodiment provides acompound of Formula (XIa) or (XIb), wherein R⁶ is chosen from optionallysubstituted C₃-C₇ carbocyclyloxy. Another embodiment provides a compoundof Formula (XIa) or (XIb), wherein R⁶ is chosen from optionallysubstituted C₄-C₁₂ carbocyclylalkyl. Another embodiment provides acompound of Formula (XIa) or (XIb), wherein R⁶ is chosen from optionallysubstituted C₄-C₁₂ carbocyclylalkoxy. Another embodiment provides acompound of Formula (XIa) or (XIb), wherein R⁶ is chosen from optionallysubstituted C₁-C₆ alkynyl. Another embodiment provides a compound ofFormula (XIa) or (XIb), wherein R⁶ is chosen from optionally substitutedC₁-C₆ alkenyl. Another embodiment provides a compound of Formula (XIa)or (XIb), wherein R⁶ is chosen from optionally substituted C₆-C₁₀ aryl.Another embodiment provides a compound of Formula (XIa) or (XIb),wherein R⁶ is chosen from optionally substituted C₆-C₁₀ aryloxy. Anotherembodiment provides a compound of Formula (XIa) or (XIb), wherein R⁶ ischosen from optionally substituted C₆-C₁₀ aryl-S—. Another embodimentprovides a compound of Formula (XIa) or (XIb), wherein R⁶ is chosen fromoptionally substituted C₇-C₁₄ aralkoxy. Another embodiment provides acompound of Formula (XIa) or (XIb), wherein R⁶ is chosen from optionallysubstituted heteroaryl. Another embodiment provides a compound ofFormula (XIa) or (XIb), wherein R⁶ is chosen from optionally substitutedheteroaryloxy.

One embodiment provides a compound, or pharmaceutically acceptable saltthereof, chosen from:

One embodiment provides a compound, or pharmaceutically acceptable saltthereof, chosen from:

One embodiment provides a compound, or pharmaceutically acceptable saltthereof, chosen from:

One embodiment provides a compound, or pharmaceutically acceptable saltthereof, chosen from:

In some embodiments, the substituted aminopyridine or aminopyridazinederivative compound as described herein, or a carboxylic acid ester, orcarboxylic acid bioisostere thereof, has the structure provided in Table1.

TABLE 1 Chemical Synthesis Example Structure Name  1

3-(benzylamino)pyridazine-4-carboxylic acid  2

3-[(2-fluorobenzyl)amino]pyridine-4- carboxylic acid  3

3-[(3-fluorobenzyl)amino]pyridine-4- carboxylic acid  4

3-[(4-fluorobenzyl)amino]pyridine-4- carboxylic acid  5

3-[(4-cyanobenzyl)amino]pyridine-4- carboxylic acid  6

3-{[4-hydroxymethyl)benzyl]amino} pyridine-4-carboxylic acid  7

3-[(4-methoxybenzyl)amino]pyridine-4- carboxylic acid  8

3-{[4-(trifluoromethyl)benzyl]amino} pyridine-4-carboxylic acid  9

3-[(biphenyl-4-ylmethyl)amino]pyridine-4- carboxylic acid  10

3-[(4-chlorobenzyl)amino]pyridine-4- carboxylic acid  11

3-{[4-(propan-2-yloxy)benzyl]amino} pyridine-4-carboxylic acid  12

3-[(4-phenoxybenzyl)amino]pyridine-4- carboxylic acid  13

3-({2-[(dimethylamino)methyl]benzyl} amino)pyridine-4-carboxylic acid 14

3-[(3,4-dichlorobenzyl)amino]pyridine-4- carboxylic acid  15

3-[(4-chloro-2-methylbenzyl)amino]pyridine- 4-carboxylic acid  16

3-[(2,4-dimethyoxybenzyl)amino]pyridine-4- carboxylic acid  17

3-[(2-hydroxybenzyl)amino]pyridine-4- carboxylic acid  18

3-[(2,4-dichlorobenzyl)amino]pyridine-4- carboxylic acid  19

3-[(2-cyclopropylbenzyl)amino]pyridine-4- carboxylic acid  20

3-[(4-chloro-2-methoxybenzyl)amino] pyridine-4-carboxylic acid  21

3-[(4-chloro-2-hydroxybenzyl)amino] pyridine-4-carboxylic acid  22

3-[(2-aminobenzyl)amino]pyridine-4- carboxylic acid  23

3-[(4-bromobenzyl)amino]pyridine-4- carboxylic acid  24

3-[(4-methylbenzyl)amino]pyridine-4- carboxylic acid  25

3-[(4-cyclopropylbenzyl)amino]pyridine-4- carboxylic acid  26

3-[(4-chloro-2-cyclopropylbenzyl)amino] pyridine-4-carboxylic acid  27

3-{[2-cyclopropyl-4- (trifluoromethl)benzyl]amino}pyridine-4- carboxylicacid  28

3-[(naphthalene-1-ylmethyl)amino]pyridine- 4-carboxylic acid  29

3-[(1H-indol-7-ylmethyl)amino]pyridine-4- carboxylic acid  30

3-[(2-cyclopropyl-3-methylbenzyl)amino] pyridine-4-carboxylic acid  31

3-{[(4-cyclopropylpyridin-3-yl)-methyl] amino}pyridine-4-carboxylic acid 32

3-{[3-(trifluoromethyl)benzyl]amino} pyridine-4-carboxylic acid  33

3-[(2-phenoxybenzyl)amino]pyridine- 4-carboxylic acid  34

3-[(2-cyclopropyl-5-methylbenzyl)amino] pyridine-4-carboxylic acid  35

3-{[3-(trifluoromethoxy)benzyl]amino} pyridine-4-carboxylic acid  36

3-{[2-(phenylaminol)benzyl]amino} pyridine-4-carboxylic acid  37

3-{[3-(cyclopropylmethoxy)benzyl]amino} pyridine-4-carboxylic acid  38

3-[(1-benzofuran-3-ylmethyl)amino] pyridine-4-carboxylic acid  39

3-{[(5-methylthiophen-2-yl)methyl]amino} pyridine-4-carboxylic acid  40

3-{[(5-methylfuran-2-yl)methyl]amino} pyridine-4-carboxylic acid  41

3-[(1-benzofuran-2-ylmethyl)amino] pyridine-4-carboxylic acid  42

3-[(adamantan-1-ylmethyl)amino]pyridine- 4-carboxylic acid  43

3-[(2,3-dihydro-1-benzofuran-2-ylmethyl) amino]pyridine-4-carboxylicacid  44

3-[(2,3-dihydro-1,4-benzodioxin-2-yl-methyl)-amino]pyridine-4-carboxylic acid  45

3-[(2,3-dihydro-1H-inden-1-yl- methylbenzyl)-amino]-pyridine-4-carboxylic acid  46

3-[(1,2,3,4-tetrahydronaphthalen-1-yl-methyl)amino]-pyridine-4-carboxylic acid  47

3-{[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl-methyl]amino}-pyridine-4-carboxylic acid  48

3-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl-methyl]-amino}pyridine-4-carboxylic acid  49

3-{[(1-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)methyl]-amino}pyridine-4-carboxylic acid  50

3-{[(7-fluoro-1,2,3,4- tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid  51

3-{[(7-fluoro-3,4-dihydronaphthalen-1- yl)methyl]-amino}pyridine-4-carboxylic acid  52

3-{[(5,7-dimethyl-1,2,3,4- tetrahydronaphthalen-1-yl)-methyl]amino}pyridine-4-carboxylic acid  53

3-{[(7-cyclopropyl-1,2,3,4- tetrahydronaphthalen-1-yl)-methyl]amino}pyridine-4-carboxylic acid  54

3-{[(5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-methyl]amino}pyridine-4-carboxylic acid  55

3-{[(5-fluoro-1-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid  56

3-({[(1S)-5-fluoro-1,2,3,4- tetrahydronaphthalen-1-yl]-methyl}amino)pyridine-4-carboxylic acid  57

3-({[(1R)-5-fluoro-1,2,3,4- tetrahydronaphthalen-1-yl]-methyl}amino)pyridine-4-carboxylic acid  58

3-[(3,4-dihydro-2H-chromen-4-ylmethyl) amino]pyridine-4-carboxylic acid 59

3-{[(4,4-dimethyl-1,2,3,4- tetrahydronaphthalen-1-yl)-methyl]amino}pyridine-4-carboxylic acid  60

3-{[(6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-methyl]amino}pyridine-4-carboxylic acid  61

3-({[(1S)-6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl]-methyl}amino)pyridine-4-carboxylic acid  62

3-({[(1R)-6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl]-methyl}amino)pyridine-4-carboxylic acid  63

3-{[(6-methyl-3,4-dihydro-2H-chromen-4-yl)methyl]-amino}pyridine-4-carboxylic acid  64

3-({[(6-(propan-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino) pyridine-4-carboxylic acid  65

3-{[(7-fluoro-3,4-dihydro-2H-chromen-4-yl)methyl]-amino}pyridine-4-carboxylic acid  66

3-{[(7-chloro-3,4-dihydro-2H-chromen-4-yl)methyl]-amino}pyridine-4-carboxylic acid  67

3-{[(6-chloro-1-hydroxy-1,2,3,4- tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid  68

3-{[(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]-amino}pyridine-4- carboxylic acid  69

3-{[(7-phenyl-3,4-dihydro-2H-chromen-4-yl)methyl]-amino}pyridine-4-carboxylic acid  70

3-{[(7-fluoro-3,4-dihydro-2H-chromen-4-yl)methyl]-amino}pyridine-4-carboxylic acid  71

3-{[(8-fluoro-3,4-dihydro-2H-chromen-4-yl)methyl]-amino}pyridine-4-carboxylic acid  72

3-{[(7-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]-amino}pyridine-4- carboxylic acid  73

3-{[(7-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)methyl]-amino}pyridine-4-carboxylic acid  74

3-{[(5-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-methyl]amino}pyridine-4-carboxylic acid  75

3-{[(7-cyclopropyl-3,4-dihydro-2H-chromen-4-yl)-methyl]amino}pyridine-4-carboxylic acid  76

3-({[(5-(cyclopropylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino) pyridine-4-carboxylic acid  77

3-{[(5-phenoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-methyl]amino}pyridine-4-carboxylic acid  78

3-[(3,4-dihydro-2H-thiochromen-4-yl- methyl)amino]pyridine-4-carboxylicacid  79

3-({[(6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino) pyridine-4-carboxylic acid  80

3-{[(5-phenoxy-1,2,3,4- tetrahydronaphthalen-1-yl)-methyl]amino}pyridine-4- carboxylic acid  81

3-({[(6-(cyclopropylmethoxy)-1,2,3,4- tetrahydro-naphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid  82

3{[(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)methyl]-amino}pyridine-4-carboxylic acid  83

3-({[(4S)-7-phenyl-3,4-dihydro-2H-chromen-4-yl]-methyl}amino)pyridine-4-carboxylic acid  84

3-({[(4R)-7-phenyl-3,4-dihydro-2H-chromen-4-yl]-methyl}amino)pyridine-4-carboxylic acid  85

3-({[(4S)-7-(3-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]-methyl}amino)pyridine- 4-carboxylic acid  86

3-({[(4R)-7-(3-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine- 4-carboxylic acid  87

3-({[(4S)-7-cyclopropyl-3,4-dihydro-2H- chromen-4-yl]-methyl}amino)pyridine-4-carboxylic acid  88

3-({[(4R)-7-cyclopropyl-3,4-dihydro-2H- chromen-4-yl]-methyl}amino)pyridine-4-carboxylic acid  89

3-({[6-(2-phenylethoxy)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid  90

3-({[6-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl} amino)pyridine-4-carboxylic acid  91

3-({[7-(2-cyclopropylethyl)-3,4-dihydro- 2H-chromen-4-yl]-methyl}amino)pyridine-4-carboxylic acid  92

3-({[6-(trifluoromethoxy)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid  93

3-({[(4S)-7-(4-fluorophenyl)-3,4-dihydro- 2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid  94

3-({[(4R)-7-(4-fluorophenyl)-3,4-dihydro- 2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid  95

3-({[(4S)-7-(2-fluorophenyl)-3,4-dihydro- 2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid  96

3-({[(4R)-7-(2-fluorophenyl)-3,4-dihydro- 2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid  97

3-({[(1S)-6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino) pyridine-4-carboxylic acid  98

3-({[(1R)-6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino) pyridine-4-carboxylic acid  99

3-({[(1S)-6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino) pyridine-4-carboxylic acid 100

3-({[(1R)-6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino) pyridine-4-carboxylic acid 101

3-({[6-(3,3,3-trifluoropropoxy)-1,2,3,4-tctrahydronaphthalen-1-yl]methyl}amino) pyridazine-4-carboxylic acid 102

3-{[(5-fluoro-6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 103

3-{[(5,6-dimethyl-1,2,3,4- tetrahydronaphthalen-1-yl)-methyl]amino}pyridine-4-carboxylic acid 104

3-{[(6-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydronaphthalen- 1-yl)methyl]amino}pyridine-4-carboxylic acid

In some embodiments, the substituted aminopyridine or aminopyridazinederivative compound as described herein, or a carboxylic acid ester, orcarboxylic acid bioisostere thereof, has the structure provided in Table2.

TABLE 2

Preparation of the Substituted Pyridine and Pyridazine DerivativeCompounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Suitable reference books andtreatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references toarticles that describe the preparation, include for example, SYNTHETICORGANIC CHEM., John Wiley & Sons, Inc., New York; Sandler et al.,ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd Ed., Academic Press, NewYork, 1983; House, MODERN SYNTHETIC REACTIONS, 2nd Ed., W. A. Benjamin,Inc. Menlo Park, Calif. 1972; Gilchrist, HETEROCYCLIC CHEM., 2nd Ed.,John Wiley & Sons, New York, 1992; March, ADVANCED ORGANIC CHEMISTRY:REACTIONS, MECHANISMS & STRUCTURE, 4th Ed., Wiley-Interscience, NewYork, 1992. Additional suitable reference books and treatise that detailthe synthesis of reactants useful in the preparation of compoundsdescribed herein, or provide references to articles that describe thepreparation, include for example, Fuhrhop & Penzlin, ORGANIC SYNTHESIS:CONCEPTS, METHODS, STARTING MATERIALS, Second, Revised and EnlargedEdition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, ORGANICCHEM., AN INTERMEDIATE TEXT (1996) Oxford Univ. Press, ISBN0-19-509618-5; Larock, R. C. COMPREHENSIVE ORGANIC TRANSFORMATIONS: AGUIDE TO FUNCTIONAL GROUP PREPARATIONS, 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; Otera (editor) MODERN CARBONYL CHEM. (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, PATAI'S 1992 GUIDE TO THE CHEM.OF FUNCTIONAL GROUPS (1992) Interscience ISBN: 0-471-93022-9; Solomons,ORGANIC CHEM. 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0;Stowell, INTERMEDIATE ORGANIC CHEM. 2nd Edition (1993)Wiley-Interscience, ISBN: 0-471-57456-2; INDUSTRIAL ORGANIC CHEMICALS:STARTING MATERIALS AND INTERMEDIATES: AN ULLMANN'S ENCYCLO. (1999) JohnWiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; ORGANIC REACTIONS(1942-2000) John Wiley & Sons, in over 55 volumes; and CHEM. OFFUNCTIONAL GROUPS, John Wiley & Sons, in 73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the substituted amidopyridine andamindopyridazine derivative compounds described herein is Stahl &Wermuth, HANDBOOK OF PHARMACEUTICAL SALTS, Verlag Helvetica ChimicaActa, Zurich, 2002.

The substituted pyridine and pyridazine derivative compounds areprepared by the general synthetic routes described below in Schemes 1-5.

Referring to Scheme 1, compound A and an amine compound B are mixed andtreated under a variety of conditions to form compound C. For example,the mixture of compound A and an amine B can be subjected to microwaveirradiation in an appropriate solvent, at temperatures ranging from 120°C. to 172° C. The ester compound E can be prepared from compound C andan alcohol D using a coupling reagent, such as HATU, in the presence ofa base.

Referring to Scheme 2, compound F and an aldehyde compound G are mixedand treated under reductive amination conditions to form compound C. Theester compound E can be prepared from compound C and an alcohol D usinga coupling reagent, such as HATU, in the presence of a base.

Referring to Scheme 3, compound H and an amine compound B are mixed andtreated under a variety of conditions to form compound E. For example,the mixture of compound H and an amine B can be subjected to a Buchwaldreaction under microwave irradiation in an appropriate solvent, attemperatures ranging from 100° C. to 120° C. The ester compound E can behydrolyzed to give compound C, using basic conditions such as 1N aq.NaOH.

Referring to Scheme 4, compound C can be used to prepare hydroxamic acidderivatives such as compound M. Treatment of compound C withhydroxylamine hydrochloride in the presence of an acid coupling reagent,such as HATU, in a solvent, such as DMF, for 1 to 24 hours providescompound M. Compound C can also be used to prepare N-acylcyanamides suchas compound N. Treatment of compound C with cyanamide in the presence ofan acid coupling reagent, such as HATU, in a solvent, such as DMF, for 1to 24 hours provides compound N.

Referring to Scheme 5, compound P can be used to prepare tetrazolederivatives such as compound Q. Treatment of compound P with sodiumazide and ammonium chloride in DMF followed by heating to 90° C. for 2to 24 hours provides the desired tetrazole derivative Q.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Pharmaceutical Compositions

In certain embodiments, a substituted amidopyridine or amidopyridazinederivative compound as described by Formulas (I), (III), (V), (XI),(XIa), (XIb), (XIII), or (XV) is administered as a pure chemical. Inother embodiments, the substituted amidopyridine or amidopyridazinederivative compound as described by Formulas (I), (III), (V), (XI),(XIa), (XIb), (XIII), or (XV) is combined with a pharmaceuticallysuitable or acceptable carrier (also referred to herein as apharmaceutically suitable (or acceptable) excipient, physiologicallysuitable (or acceptable) excipient, or physiologically suitable (oracceptable) carrier) selected on the basis of a chosen route ofadministration and standard pharmaceutical practice as described, forexample, in REMINGTON: SCIENCE & PRACTICE OF PHARMACY (Gennaro, 21st Ed.Mack Pub. Co., Easton, Pa. (2005)), the disclosure of which is herebyincorporated herein by reference, in its entirety.

Accordingly, provided herein is a pharmaceutical composition comprisingat least one substituted amidopyridine or amidopyridazine derivativecompound, or a stereoisomer, prodrug, pharmaceutically acceptable salt,hydrate, solvate, or N-oxide thereof, together with one or morepharmaceutically acceptable carriers and, optionally, other therapeuticand/or prophylactic ingredients. The carrier(s) (or excipient(s)) isacceptable or suitable if the carrier is compatible with the otheringredients of the composition and not deleterious to the recipient(i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formulas (I),(III), (V), (XI), (XIa), (XIb), (XIII), or (XV), or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof.

In certain embodiments, the substituted amidopyridine or amidopyridazinederivative compound as described by Formulas (I), (III), (V), (XI),(XIa), (XIb), (XIII), or (XV) is substantially pure, in that it containsless than about 5%, or less than about 1%, or less than about 0.1%, ofother organic small molecules, such as contaminating intermediates orby-products that are created, for example, in one or more of the stepsof a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. See, e.g., REMINGTON: SCIENCE & PRACTICE OFPHARMACY (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa. (2005).

The dose of the composition comprising at least one substitutedamidopyridine or amidopyridazine derivative compound as described hereinmay differ, depending upon the patient's (e.g., human) condition, thatis, stage of the disease, general health status, age, and other factorsthat a person skilled in the medical art will use to determine dose.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. The optimal dose may depend upon the bodymass, weight, or blood volume of the patient.

Oral doses can typically range from about 1.0 mg to about 1000 mg, oneto four times, or more, per day.

Histone Demethylase

Chromatin is the complex of DNA and protein that makes up chromosomes.Histones are the major protein component of chromatin, acting as spoolsaround which DNA winds. Changes in chromatin structure are affected bycovalent modifications of histone proteins and by non-histone bindingproteins. Several classes of enzymes are known which can covalentlymodify histones at various sites.

Proteins can be post-translationally modified by methylation on aminogroups of lysines and guanidino groups of arginines or carboxymethylatedon aspartate, glutamate, or on the C-terminus of the protein.Post-translational protein methylation has been implicated in a varietyof cellular processes such as RNA processing, receptor mediatedsignaling, and cellular differentiation. Post-translational proteinmethylation is widely known to occur on histones, such reactions knownto be catalyzed by histone methyltransferases, which transfer methylgroups from S-adenyosyl methionine (SAM) to histones. Histonemethylation is known to participate in a diverse range of biologicalprocesses including heterochromatin formation, X-chromosomeinactivation, and transcriptional regulation. Lachner et al., (2003) J.Cell Sci. 116:2117-2124; Margueron et al., (2005) Curr. Opin. Genet.Dev. 15:163-176.

Unlike acetylation, which generally correlates with transcriptionalactivation, whether histone methylation leads to transcriptionactivation or repression depends on the particular site of methylationand the degree of methylation (e.g., whether a particular histone lysineresidue is mono-, di-, or tri-methylated). However, generally,methylation on H3K9, H3K27 and H4K20 is linked to gene silencing, whilemethylation on H3K4, H3K36, and H3K79 is generally associated withactive gene expression. In addition, tri- and di-methylation of H3K4generally marks the transcriptional start sites of actively transcribedgenes, whereas mono-methylation of H3K4 is associated with enhancersequences.

A “demethylase” or “protein demethylase,” as referred to herein, refersto an enzyme that removes at least one methyl group from an amino acidside chain. Some demethylases act on histones, e.g., act as a histone H3or H4 demethylase. For example, an H3 demethylase may demethylate one ormore of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4demethylase may demethylate histone H4K20. Demethylases are known whichcan demethylate either a mono-, di- and/or a tri-methylated substrate.Further, histone demethylases can act on a methylated core histonesubstrate, a mononucleosome substrate, a dinucleosome substrate and/oran oligonucleosome substrate, peptide substrate and/or chromatin (e.g.,in a cell-based assay).

The first lysine demethylase discovered was lysine specific demethylase1 (LSD1/KDM1), which demethylates both mono- and di-methylated H3K4 orH3K9, using flavin as a cofactor. A second class of Jumonji C (JmjC)domain containing histone demthylases were predicted, and confirmed whena H3K36 demethylase was found using a formaldehyde release assay, whichwas named JmjC domain containing histone demethylase 1 (JHDM1/KDM2A).

More JmjC domain-containing proteins were subsequently identified andthey can be phylogenetically clustered into seven subfamilies: JHDM1,JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC domain only.

JMJD2 Family

The JMJD2 family of proteins are a family of histone-demethylases knownto demethylate tri- and di-methylated H3-K9, and were the firstidentified histone tri-methyl demethylases. In particular, ectopicexpression of JMJD2 family members was found to dramatically decreaselevels of tri-and di-methylated H3-K9, while increasing levels ofmono-methylated H3-K9, which delocalized Heterochromatin Protein 1 (HP1)and reduced overall levels of heterochromatin in vivo. Members of theJMJD2 subfamily of jumonji proteins include JMJD2C and its homologuesJMJD2A, JMJD2B, JMJD2D and JMJD2E. Common structural features found inthe JMJD2 subfamily of Jumonji proteins include the JmjN, JmjC, PHD andTdr sequences.

JMJD2C, also known as GASC1 and KDM4C, is known to demethylatetri-methylated H3K9 and H3K36. Histone demethylation by JMJD2C occursvia a hydroxylation reaction dependent on iron and α-ketoglutarate,wherein oxidative decarboxylation of α-ketoglutarate by JMJD2C producescarbon dioxide, succinate, and ferryl and ferryl subsequentlyhydroxylates a methyl group of lysine H3K9, releasing formaldehyde.JMJD2C is known to modulate regulation of adipogenesis by the nuclearreceptor PPARγ and is known to be involved in regulation of self-renewalin embryonic stem cells.

JARID Family

As used herein, a “JARID protein” includes proteins in the JARID1subfamily (e.g., JARID1A, JARID1B, JARID1C and JARID1D proteins) and theJARID2 subfamily, as well as homologues thereof. A further descriptionand listing of JARID proteins can be found in Klose et al. (2006) NatureReviews/Genetics 7:715-727. The JARID1 family contains several conserveddomains: JmjN, ARID, JmjC, PHD and a C5HC2 zing finger.

JARID1A, also called KDM5A or RBP2, was initially found as a bindingpartner of retinoblastoma (Rb) protein. JARID1A was subsequently foundto function as a demethylase of tri- and di-methylated H3K4, and hasbeen found to promote cell growth, while inhibiting senescence anddifferentiation. For instance, abrogation of JARID1A from mouse cellsinhibits cell growth, induces senescence and differentiation, and causesloss of pluripotency of embryonic stem cells in vitro. JARID1A has beenfound to be overexpressed in gastric cancer and the loss of JARID1A hasbeen found to reduce tumorigenesis in a mouse cancer model.Additionally, studies have demonstrated that loss of the retinoblastomebinding protein 2 (RBP2) histone demethylase suppresses tumorigenesis inmice lacking Rb1 or Men1 (Lin et al. P.N.A.S. Aug. 16, 2011,108(33):13379-86; doi: 10.1073/pnas.1110104108) and the authors of thestudy concluded that RBP2-inhibitory drugs would have anti-canceractivity.

JARID1B, also referred to as KDM5B and PLU1, was originally found inexperiments to discover genes regulated by the HER2 tyrosine kinase.JARID1B has consistently been found to be expressed in breast cancercell lines, although restriction of JARID1B has been found in normaladult tissues, with the exception of the testis. In addition, 90% ofinvasive ductal carcinomas have been found to express JARID1B. Inaddition, JARID1B has been found to be up-regulated in prostate cancers,while having more limited expression in benign prostate, and has alsobeen found to be up-regulated in bladder cancer and lung cancer (bothSCLC and NSCLC). JARID1B has also been found to repress tumor suppressorgenes such as BRCA1, CAV1 and 14-3-3σ, and knockdown of JARID1B wasfound to increase the levels of tri-methylated H3K4 at these genes.

In an additional embodiment is the method for inhibiting ahistone-demethylase enzyme, wherein the histone-demethylase enzymecomprises a JmjC domain. In an additional embodiment is the method forinhibiting a histone-demethylase enzyme, wherein the histone-demethylaseenzyme is selected from JARID1A, JARID1B, or JMJD2C.

Methods of Treatment

Disclosed herein are methods of modulating demethylation in a cell or ina subject, either generally or with respect to one or more specifictarget genes. Demethylation can be modulated to control a variety ofcellular functions, including without limitation: differentiation;proliferation; apoptosis; tumorigenesis, leukemogenesis or otheroncogenic transformation events; hair loss; or sexual differentiation.For example, in particular embodiments, the invention provides a methodof treating a disease regulated by histone methylation and/ordemethylation in a subject in need thereof by modulating the activity ofa demethylase comprising a JmjC domain (e.g., a histone demethylase suchas a JHDM protein(s)).

In a further embodiment is the method for treating cancer in a subjectwherein the cancer is selected from prostate cancer, breast cancer,bladder cancer, lung cancer or melanoma.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compound ofFormula (I), (III), (V), (XI), (XIa), (XIb), (XIII), or (XV), or apharmaceutically acceptable salt thereof, wherein the tumor ischaracterized by a loss of retinoblastoma gene (RB1) function.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compound ofFormula (I), (III), (V), (XI), (XIa), (XIb), (XIII), or (XV), or apharmaceutically acceptable salt thereof, wherein the tumor ischaracterized by a loss of multiple endocrine neoplasia type 1 gene(Men1) function.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

Examples

I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Example 1: 3-(benzylamino)pyridazine-4-carboxylic acid

3-Aminopyridazine-4-carboxylic acid (200 mg, 1.43 mmol) and benzaldehyde(0.18 mL, 1.73 mmol) were stirred in DMF (3 mL) at 90° C. for four days.The reaction mixture was allowed to cool to room temperature (“rt”) andsodium triacetoborohydride (605 mg, 2.86 mmol) was added. The reactionwas stirred for 16 hr. The reaction was quenched with water andextracted with EtOAc. The extracts were dried (Na₂SO₄) and concentrated.The residue was purified by column chromatography (0-20% MeOH/DCM). Therelevant fractions were concentrated to give 6.3 mg (4%) of the titlecompound. ¹H NMR (500 MHz, DMSO-d₆): δ 8.51 (d, 1H, 5 Hz), 7.63 (d, 1H,J=5.0 Hz), 7.30-7.39 (m, 4H), 7.22-7.25 (m, 1H), 4.72 (br s, 2H). [M+H]calc'd for C₁₂H₁₁N₃O₂, 230; found 230.

Example 2: 3-[(2-fluorobenzyl)amino]pyridine-4-carboxylic acid

3-Fluoroisonicotinic acid (100 mg, 0.71 mmol) and 2-fluorobenzylamine(308 μL, 2.84 mmol) were combined in ACN (3 mL) and the solution wasstirred at 158° C. in a microwave for 1 hr. The solution wasconcentrated in vacuo and purified by silica gel chromatography (10% to20% MeOH/DCM). The semi-pure fractions were concentrated and then takenup in water to give a white precipitate, which was collected byfiltration and dried under vacuum to give 18 mg (10%) of the titlecompound. ¹H NMR (500 MHz, DMSO-d₆): δ 8.18 (s, 1H), 7.99 (br s, 1H),7.84 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.31-7.41 (m, 2H),7.15-7.23 (m, 2H), 4.62 (s, 2H). [M+H] calc'd for C₁₃H₁₁FN₂O₂, 247;found 247.

Example 3: 3-[(3-fluorobenzyl)amino]pyridine-4-carboxylic acid

3-Fluoroisonicotinic acid (100 mg, 0.71 mmol) and 3-fluorobenzylamine(308 μL, 2.84 mmol) were combined in DMA (3 mL) and the solution wasstirred at 168° C. in a microwave for 90 min. The solution wasconcentrated in vacuo and purified through a short plug of silica gelchromatography (20% MeOH/DCM). The semi-pure fractions were concentratedand then taken up in water to give a white precipitate, which wascollected by filtration and dried under vacuum to give 58 mg (33%) ofthe title compound. ¹H NMR (500 MHz, DMSO-d₆): δ 8.18 (s, 1H), 7.99 (brs, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.31-7.41 (m,2H), 7.15-7.23 (m, 2H), 4.62 (s, 2H). [M+H] calc'd for C₁₃H₁₁FN₂O₂, 247;found 247.

Example 4: 3-[(4-fluorobenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 55% yield from 4-fluorobenzylamineand 4-fluoroisonicotinic acid according to the procedure for thepreparation of Example 3. ¹H NMR (500 MHz, DMSO-d₆): δ 13.45 (br s, 1H),8.11 (s, 1H), 8.03 (br s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.58 (d, 1H,J=5.0 Hz), 7.36-7.42 (m, 1H), 7.16-7.23 (m, 2H), 7.05-7.11 (m, 1H), 4.60(s, 2H). [M+H] calc'd for C₁₃H₁₁FN₂O₂, 247; found 247.

Preparation 4A: methyl 3-[(4-fluorobenzyl)amino]pyridine-4-carboxylate

Methyl 3-bromoisonicotinate (220 mg, 1.02 mmol), 4-fluorobenzylamine(132 μL, 1.22 mmol), tris(dibenzylideneacetone)dipalladium(0) (47 mg,0.051 mmol), Xantphos (89 mg, 0.153 mmol), and cesium carbonate (500 mg,1.53 mmol) were combined in dioxane (4 mL) under N₂ in a sealedmicrowave tube. The reaction mixture was heated at 116° C. in amicrowave for 1 hr. The mixture was then filtered, washing with DCM, toremove solids. The solution was concentrated in vacuo and purified bysilica gel chromatography (20-50% EtOAc/hexanes) to give 228 mg (88%) ofthe title compound as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.18 (s,1H), 7.93 (d, 1H, J=5.0 Hz), 7.79 (br s, 1H), 7.63 (d, 1H, J=5.0 Hz),7.27-7.34 (m, 2H), 7.03 (t, 2H, J=8.6 Hz), 4.47 (d, 2H, J=5.6 Hz), 3.89(s, 3H). [M+H] calc'd for C₁₄H₁₃FN₂O₂, 261; found 261.

Example 5: 3-[(4-cyanobenzyl)amino]pyridine-4-carboxylic acid

3-Fluoroisonicotinic acid (100 mg, 0.71 mmol),4-(aminomethyl)-benzonitrile hydrochloride (240 mg, 1.42 mmol), and DIEA(250 μL, 1.42 mmol) were combined in DMA (2 mL) and the reaction mixturewas stirred at 166° C. in a microwave for 90 min. The solution wasconcentrated in vacuo and purified by silica gel chromatography (10-20%MeOH/DCM). The semi-pure fractions were concentrated and then taken upin water to give a pale yellow precipitate, which was collected byfiltration and dried under vacuum to give 32 mg (18%) of the titlecompound. ¹H NMR (500 MHz, DMSO-d₆): δ 8.10 (br s, 1H), 8.04 (s, 1H),7.83 (d, 1H, J=5.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz),7.54 (d, 2H, J=8.0 Hz), 4.69 (s, 2H). [M+H] calc'd for C₁₄H₁₁N₃O₂, 254;found 254.

Preparation 5A: methyl 3-[(4-cyanobenzyl)amino]pyridine-4-carboxylate

The title compound was prepared in 4% yield from4-(aminomethyl)-benzonitrile hydrochloride and methyl3-bromoisonicotinate according to the procedure for Preparation 4A. ¹HNMR (500 MHz, CDCl₃): δ 8.07 (s, 1H), 7.97 (d, 2H, J=5.0 Hz), 7.63-7.70(m, 3H), 7.46 (d, 2H, J=8.3 Hz), 4.61 (d, 2H, J=6.1 Hz), 3.94 (s, 3H).[M+H] calc'd for C₁₅H₁₃N₃O₂, 268; found 268.

Example 6: 3-{[4-hydroxymethyl)benzyl]amino}pyridine-4-carboxylic acid

The title compound was prepared in 9% yield from (4-aminomethyl)benzylalcohol hydrochloride and 3-fluoroisonicotinic acid according to theprocedure for the preparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ8.12 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.26-7.34(m, 4H), 5.13 (t, 1H, J=1.6 Hz), 4.53 (s, 2H), 4.46 (d, 2H, J=5.2 Hz).[M+H] calc'd for C₁₄H₁₄N₂O₃, 259; found 259.

Example 7: 3-[(4-methoxybenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 26% yield from 4-methoxybenzylamineand 3-fluoroisonicotinic acid according to the procedure for thepreparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (s, 1H),7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.29 (d, 2H, J=8.5 Hz),6.91 (d, 2H, J=8.5 Hz), 4.47 (s, 2H), 3.73 (s, 3H). [M+H] calc'd forC₁₄H₁₄N₂O₃, 259; found 259.

Example 8: 3-{[4-(trifluoromethyl)benzyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 28% yield from4-(trifluoromethyl)-benzylamine and 3-fluoroisonicotinic acid accordingto the procedure for the preparation of Example 3. ¹H NMR (400 MHz,DMSO-d₆): δ 8.10 (br s, 1H), 8.04 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.81(d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 4.69(s, 2H). [M+H] calc'd for C₁₄H₁₁F₃N₂O₂, 297; found 297.

Preparation 8A: methyl3-{[4-(trifluoromethyl)benzyl]amino}pyridine-4-carboxylate

The title compound was prepared in 40% yield from4-(trifluoromethyl)benzylamine and methyl 3-bromoisonicotinate accordingto the procedure for Preparation 4A. ¹H NMR (400 MHz, CDCl₃): δ 8.12 (s,1H), 7.95 (d, 1H, J=5.0 Hz), 7.93 (br s, 1H), 7.65 (d, 1H, J=5.0 Hz),7.60 (d, 2H, J=8.1 Hz), 7.47 (d, 2H, J=8.1 Hz), 4.58 (d, 2H, J=5.9 Hz)3.91 (s, 3H). [M+H] calc'd for C₁₅H₁₃F₃N₂O₂, 311; found 311.

Example 9: 3-[(biphenyl-4-ylmethyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 36% yield from 4-phenylbenzylamineand 3-fluoroisonicotinic acid according to the procedure for thepreparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 13.55 (br s, 1H),8.17 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.71 (m, 4H), 7.58 (d, 1H, J=5.0Hz), 7.32-7.48 (m, 5H), 4.62 (s, 2H). [M+H] calc'd for C₁₉H₁₆N₂O₂, 305;found 305.

Example 10: 3-[(4-chlorobenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 32% yield from 4-chlorobenzylamineand 3-fluoroisonicotinic acid according to the procedure for thepreparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 13.45 (br s, 1H),8.04 (s, 1H), 7.76 (d, 1H, J=5.0 Hz), 7.51 (d, 1H, J=5.0 Hz), 7.29-7.36(m, 4H), 4.51 (s, 2H). [M+H] calc'd for C₁₃H₁₁ClN₂O₂, 263, 265; found263, 265.

Preparation 10A: methyl 3-[(4-chlorobenzyl)amino]pyridine-4-carboxylate

The title compound was prepared in 72% yield from 4-chlorobenzylamineand methyl 3-bromoisonicotinate according to the procedure forPreparation 4A. ¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 1H), 7.94 (d, 1H,J=5.0 Hz), 7.82 (br s, 1H), 7.62 (d, 1H, J=5.0 Hz), 7.24-7.32 (m, 4H),4.47 (d, 2H, J=5.7 Hz), 3.89 (s, 3H). [M+H] calc'd for C₁₄H₁₃ClN₂O₂,277, 279; found 277, 279.

Example 11: 3-{[4-(propan-2-yloxy)benzyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 28% yield from1-(4-isopropoxyphenyl)-methanamine and 3-fluoroisonicotinic acidaccording to the procedure for the preparation of Example 3. ¹H NMR (400MHz, DMSO-d₆): δ 8.12 (s, 1H), 7.80 (d, 1H, J=5.0 Hz), 7.56 (d, 1H,J=5.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 7.21 (d, 2H, J=8.0 Hz), 4.49 (s, 2H),2.82-2.89 (m, 1H), 1.19 (d, 6H, J=4.5 Hz). [M+H] calc'd for C₁₆H₁₈N₂O₃,287; found 287.

Example 12: 3-[(4-phenoxybenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 36% yield from 4-phenoxybenzylamineand 3-fluoroisonicotinic acid according to the procedure for thepreparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 13.42 (br s, 1H),8.18 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.35-7.40(m, 4H), 7.13 (t, 1H, J=7.2), 6.97-7.02 (m, 4H), 4.55 (s, 2H). [M+H]calc'd for C₁₉H₁₆N₂O₃, 321; found 321.

Preparation 13A: methyl3-({2-[(dimethylamino)methyl]benzyl}amino)pyridine-4-carboxylate

The title compound was prepared in 65% yield fromN-[2-(aminomethyl)benzyl]-N,N-dimethylamine and methyl3-bromoisonicotinate according to the procedure for Preparation 4A. ¹HNMR (400 MHz, CDCl₃): δ 8.27 (s, 1H), 7.88 (d, 1H, J=5.1 Hz), 7.82 (brs, 1H), 7.61 (d, 1H, J=5.1 Hz), 7.20-7.36 (m, 4H), 4.68 (d, 2H, J=5.8Hz), 3.87 (s, 3H), 3.46 (s, 2H), 2.22 (s, 6H). [M+H] calc'd forC₁₇H₂₁N₃O₂, 300; found 300.

Example 13:3-({2-[(dimethylamino)methyl]benzyl}amino)pyridine-4-carboxylic acid,formic acid salt

Preparation 13A (338 mg, 1.13 mmol) was stirred in MeOH (5 mL) with 1NNaOH (2 mL) at 40° C. for 2 hr. The solution was concentrated andpurified by prep-HPLC (0-20% ACN/water with 0.1% formic acid) to give260 mg (70%) of the title compound as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.26 (br s, 1H), 8.12 (br s, 1H), 7.88 (br s, 1H), 7.80 (d,1H, J=5.0 Hz), 7.39-7.57 (m, 4H), 4.61 (s, 2H), 4.44 (s, 2H), 2.85 (s,6H). [M+H] calc'd for C₁₆H₁₉N₃O₂, 286; found 286.

Example 14: 3-[(3,4-dichlorobenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 37% yield from3,4-dichlorobenzylamine and 3-fluoroisonicotinic acid according to theprocedure for the preparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ13.48 (br s, 1H), 8.10 (s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.57-7.65 (m,3H), 7.35 (dd, 1H, J=8.3, 1.9 Hz), 4.59 (s, 2H). [M+H] calc'd forC₁₃H₁₀Cl₂N₂O₂, 297, 299; found 297, 299.

Preparation 14A: methyl3-[(3,4-dichlorobenzyl)amino]pyridine-4-carboxylate

The title compound was prepared in 73% yield from3,4-dichlorobenzylamine and methyl 3-bromoisonicotinate according to theprocedure for Preparation 4A. ¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H),7.95 (d, 1H, J=5.1 Hz), 7.87 (br s, 1H), 7.65 (d, 1H, J=5.1 Hz), 7.42(d, 1H, J=8.7 Hz), 7.39 (s, 1H), 7.18 (dd, 1H, J=8.2 Hz), 4.48 (d, 2H,J=6.0 Hz), 3.91 (s, 3H). [M+H] calc'd for C₁₄H₁₂Cl₂N₂O₂, 311, 313; found311, 313.

Example 15: 3-[(4-chloro-2-methylbenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 45% yield from4-chloro-2-methylbenzylamine and 3-fluoroisonicotinic acid according tothe procedure for the preparation of Example 3. ¹H NMR (400 MHz,DMSO-d₆): δ 13.50 (br s, 1H), 8.10 (s, 1H), 7.85 (d, 1H, J=5.0 Hz), 7.61(br s, 1H), 7.59 (d, 1H, J=5.0 Hz), 7.31 (s, 1H), 7.19-7.25 (m, 2H),4.52 (s, 2H), 2.34 (s, 3H). [M+H] calc'd for C₁₄H₁₃ClN₂O₂, 277, 279;found 277, 279.

Example 16: 3-[(2,4-dimethyoxybenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 61% yield from2,4-dimethoxybenzylamine and 3-fluoroisonicotinic acid according to theprocedure for the preparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ13.41 (br s, 1H), 8.20 (s, 1H), 7.80 (d, 1H, J=5.0 Hz), 7.54 (d, 1H,J=5.0 Hz), 7.18 (d, 1H, J=8.3 Hz), 6.59 (d, 1H, J=2.4 Hz), 6.48 (dd, 1H,J=8.3, 2.4 Hz), 4.40 (s, 2H), 382 (s, 3H), 3.74 (s, 3H). [M+H] calc'dfor C₁₅H₁₆N₂O₄, 259; found 259.

Example 17: 3-[(2-hydroxybenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 2% yield from 2-(aminomethyl)phenoland 3-fluoroisonicotinic acid according to the procedure for thepreparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 13.30 (br s, 1H),9.67 (s, 1H), 8.20 (s, 1H), 7.79 (d, 1H, J=4.9 Hz), 7.54 (d, 1H, J=4.9Hz), 7.20 (d, 1H, J=7.0 Hz), 7.09 (t, 1H, J=7.6 Hz), 6.84 (d, 1H,J=8.1), 6.84 (dd, 1H, J=7.4 Hz), 4.44 (s, 2H). [M+H] calc'd forC₁₃H₁₂N₂O₃, 245; found 245.

Example 18: 3-[(2,4-dichlorobenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 42% yield from2,4-dichlorobenzylamine and 3-fluoroisonicotinic acid according to theprocedure for the preparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ13.49 (br s, 1H), 8.04 (s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.66 (s, 1H),7.59 (d, 1H, J=5.0 Hz), 7.38-7.42 (m, 2H), 4.63 (s, 2H). [M+H] calc'dfor C₁₃H₁₀Cl₂N₂O₂, 297, 299; found 297, 299.

Preparation 19A: 3-[(2-bromobenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 33% yield from 2-bromobenzylamine and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. [M+H] calc'd for C₁₃H₁₁BrN₂O₂, 307, 309; found 307, 309.

Preparation 19B: methyl 3-[(2-bromobenzyl)amino]pyridine-4-carboxylate

Preparation 19A (202 mg, 0.66 mmol) was stirred in DMF (5 mL) with MeOH(0.5 mL). Triethylamine (120 μL, 0.86 mmol) and then HATU (300 mg, 0.79mmol) were added, and the reaction stirred for 1 hr. The solution wasconcentrated and purified by silica gel chromatography (20%-80%EtOAc/hexanes) to give 128 mg (60%) of the title compound as a whitesolid. ¹H NMR (400 MHz, CDCl₃): δ 8.21 (s, 1H), 7.94 (d, 1H, J=5.0 Hz),7.91 (br s, 1H), 7.65 (d, 1H, J=5.0 Hz), 7.59 (dd, 1H, J=7.9, 1.0 Hz),7.24-7.35 (m, 2H), 7.14 (td, 1H, J=7.8, 1.6 Hz), 4.59 (d, 2H, J=6.1 Hz),3.92 (s, 3H). [M+H] calc'd for C₁₄H₁₃BrN₂O₂, 321, 323; found 321, 323.

Preparation 19C: methyl3-[(2-cyclopropylbenzyl)amino]pyridine-4-carboxylate

Potassium phosphate (119 mg, 0.56 mmol), palladium acetate (4.2 mg,0.019 mmol) and tricyclohexylphosphine (10.4 mg, 0.037 mmol) werecombined in toluene (3 mL) with water (0.15 mL) under N₂. Preparation19B (120 mg, 0.37 mmol) and cyclopropylboronic acid (48 mg, 0.56 mmol)were added, and the reaction stirred at 142° C. in a microwave for 1 hr.The reaction mixture was diluted with DCM, dried (MgSO₄) andconcentrated in vacuo. Purification by silica gel chromatography (20-60%EtOAc/DCM) gave 88 mg (84%) of the title compound as a white solid. ¹HNMR (400 MHz, CDCl₃): δ 8.22 (s, 1H), 7.91 (d, 1H, J=5.0 Hz), 7.73 (brs, 1H), 7.63 (d, 1H, J=5.0 Hz), 7.13-7.31 (m, 3H), 7.07 (d, 1H, J=7.7Hz), 4.67 (d, 2H, J=5.6 Hz), 3.87 (s, 3H), 1.92-1.97 (m, 1H), 0.93-0.98(m, 2H), 0.69-0.74 (m, 2H). [M+H] calc'd for C₁₇H₁₈N₂O₂, 283; found 283.

Example 19: 3-[(2-cyclopropylbenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 46% yield from Preparation 19Caccording to the general hydrolysis procedure outlined for Example 13.¹H NMR (400 MHz, DMSO-d₆): δ 13.42 (br s, 1H), 8.17 (s, 1H), 7.84 (d,1H, J=5.0 Hz), 7.61 (br s, 1H), 7.58 (d, 1H, J=5.0 Hz), 7.12-7.27 (m,3H), 7.04 (d, 1H, J=7.1 Hz), 4.70 (s, 2H), 1.99-2.09 (m, 1H), 0.90-0.96(m, 2H), 0.65-0.69 (m, 2H). [M+H] calc'd for C₁₆H₁₆N₂O₂, 269; found 269.

Example 20: 3-[(4-chloro-2-methoxybenzyl)amino]pyridine-4-carboxylicacid

The title compound was prepared in 35% yield from4-chloro-2-methoxy-benzylamine and 3-fluoroisonicotinic acid accordingto the procedure for the preparation of Example 3. ¹H NMR (400 MHz,DMSO-d₆): δ 13.49 (br s, 1H), 8.10 (s, 1H), 8.00 (br s, 1H), 7.81 (d,1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.24 (d, 1H, J=8.1 Hz), 7.11 (d,1H, J=1.9 Hz), 6.96 (dd, 1H, J=8.0, 1.9 Hz), 4.47 (s, 2H), 3.87 (s, 3H).[M+H] calc'd for C₁₄H₁₃ClN₂O₃, 293, 295; found 293, 295.

Example 21: 3-[(4-chloro-2-hydroxybenzyl)amino]pyridine-4-carboxylicacid

Example 20 (50 mg, 0.17 mmol) was stirred in DCM (10 mL) at 0° C. BBr₃(0.51 mL, 1.0 M, 0.51 mmol) was added, and the reaction stirred for 2 hrwhile warming to rt. The solution was poured over a mixture of 1N NaOH(10 mL) and MeOH (10 mL), and the solution was concentrated in vacuo.Purification by prep-HPLC (5-95% ACN/water with 0.05% formic acid) gave8 mg (17%) of the title compound as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 10.29 (br s, 1H), 8.16 (br s, 1H), 8.09 (br s, 1H),7.79 (br s, 1H), 7.56 (br s, 1H), 7.19 (d, 1H, J=8.1 Hz), 6.87 (d, 1H,J=2.0 Hz), 6.80 (dd, 1H, J=8.1, 2.0 Hz) 4.40 (s, 2H). [M+H] calc'd forC₁₃H₁₁ClN₂O₃, 279, 281; found 279, 281.

Example 22: 3-[(2-aminobenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 9% yield from 2-aminobenzylamine and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 8.16 (s, 1H), 7.82 (d, 1H,J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.05 (d, 1H, J=7.5 Hz), 6.97 (td, 1H,J=7.8, 1.4 Hz), 6.66 (d, 1H, J=7.9 Hz), 6.52 (td, 1H, J=7.4, 1.0 Hz),4.35 (s, 2H). [M+H] calc'd for C₁₃H₁₃N₃O₂, 244; found 244.

Example 23: 3-[(4-bromobenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 39% yield from 4-bromobenzylamine and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 13.55 (br s, 1H), 8.08 (s,1H), 7.82 (d, 1H, J=5.0 Hz), 7.52-7.58 (m, 3H), 7.32 (d, 2H, J=8.3 Hz),4.55 (s, 2H). [M+H] calc'd for C₁₃H₁₁BrN₂O₂, 307, 309; found 307, 309.

Example 24: 3-[(4-methylbenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 51% yield from 4-methylbenzylamineand 3-fluoroisonicotinic acid according to the procedure for thepreparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 13.41 (br s, 1H),8.13 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.25 (d,2H, J=7.9 Hz), 7.15 (d, 2H, J=7.8 Hz), 4.50 (s, 2H), 2.28 (s, 3H). [M+H]calc'd for C₁₄H₁₄N₂O₂, 243; found 243.

Preparation 25A: methyl 3-[(4-bromobenzyl)amino]pyridine-4-carboxylate

The title compound was prepared in 87% yield from Example 23 accordingto the procedure for Preparation 19B. ¹H NMR (400 MHz, DMSO-d₆): δ 13.47(br s, 1H), 8.14 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0Hz), 7.23 (d, 2H, J=8.0 Hz), 7.04 (d, 2H, J=8.0 Hz), 4.49 (s, 2H),1.86-1.91 (m, 1H), 0.89-0.94 (m, 2H), 0.60-0.65 (m, 2H). [M+H] calc'dfor C₁₆H₁₆N₂O₂, 269; found 269.

Preparation 25B: methyl3-[(4-cyclopropylbenzyl)amino]pyridine-4-carboxylate

The title compound was prepared in 82% yield from Preparation 25Aaccording to the general procedure for Preparation 19C. ¹H NMR (400 MHz,CDCl₃): δ 8.21 (s, 1H), 7.91 (d, 1H, J=5.0 Hz), 7.75 (br s, 1H), 7.62(d, 1H, J=5.0 Hz), 7.23 (d, 2H, J=8.2 Hz), 7.04 (d, 2H, J=8.2 Hz), 4.46(d, 2H, J=5.6 Hz), 3.89 (s, 3H), 1.84-1.91 (m, 1H), 0.92-0.98 (m, 2H),0.64-0.70 (m, 2H). [M+H] calc'd for C₁₇H₁₈N₂O₂, 283; found 283.

Example 25: 3-[(4-cyclopropylbenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 35% yield from Preparation 25Baccording to the general hydrolysis procedure outlined for Example 13.¹H NMR (400 MHz, DMSO-d₆): δ 13.47 (br s, 1H), 8.14 (s, 1H), 7.81 (d,1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.23 (d, 2H, J=8.0 Hz), 7.04 (d,2H, J=8.0 Hz), 4.49 (s, 2H), 1.86-1.91 (m, 1H), 0.89-0.94 (m, 2H),0.60-0.65 (m, 2H). [M+H] calc'd for C₁₆H₁₆N₂O₂, 269; found 269.

Preparation 26A: 4-chloro-2-cyclopropyl-benzonitrile

The title compound was prepared in 82% yield from2-bromo-4-chloro-benzonitrile according to the general procedure forPreparation 19C. ¹H NMR (400 MHz, CDCl₃): δ 0.79-0.84 (2H, m), 1.16-1.21(2H, m), 2.25-2.29 (1H, m), 6.91 (1H, d, J=2.0 Hz), 7.21 (1H, dd, J=2.0,8.4 Hz), 7.51 (1H, d, J=8.4 Hz).

Preparation 26B: 4-chloro-2-cyclopropyl-benzylamine

To a solution Preparation 26A (1.0 g, 5.7 mmol) in THF (20 mL) was addedLiAlH₄ (11.3 mL, 1.0 M) at rt, and the reaction was stirred for 2 h. Thereaction mixture was cooled to 0° C. and slowly diluted with water (0.5mL), 15% NaOH (0.5 mL), and water (1.5 mL). The reaction was filteredthrough Celite and concentrated to give 900 mg (71%) of the crude titlecompound as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 0.66-0.70 (2H, m),0.95-1.00 (2H, m), 1.93-1.97 (1H, m), 6.95 (1H, d, J=2.0 Hz), 7.14 (1H,dd, J=2.0, 8.4 Hz), 7.24 (1H, d, J=8.4 Hz).

Example 26:3-[(4-chloro-2-cyclopropylbenzylbenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 3% yield from Preparation 26B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 0.71-0.75 (2H, m), 0.93-0.98(2H, m), 2.02-2.09 (1H, m), 4.70 (2H, s), 7.06 (1H, s), 7.19-7.27 (2H,m), 7.60 (1H, d, J=4.8 Hz), 7.85-7.90 (2H, m), 8.13 (1H, s). [M+H]Calc'd for C₁₆H₁₅ClN₂O₂, 303; found, 303.

Preparation 26C: methyl3-[(4-chloro-2-cyclopropylbenzyl)amino]pyridine-4-carboxylate

To a solution of Example 26 (15 mg, 0.05 mmol) in MeOH (10 mL) was addedthionyl chloride (1 mL) at rt. The reaction was stirred at reflux for 2days. The solution was concentrated and purified by prep-HPLC to give 5mg (31%) of the title compound as a yellow solid. ¹H NMR (400 MHz,CD₃OD): δ 0.70-0.73 (2H, m), 1.0-1.04 (2H, m), 2.0-2.04 (1H, m), 3.96(2H, s), 4.74 (3H, s), 7.08 (1H, d, J=1.6 Hz), 7.14 (1H, dd, J=2.0, 8.4Hz), 7.25 (1H, d, J=8.0 Hz), 7.91 (1H, d, J=4.0 Hz), 8.05 (1H, d, J=5.6Hz), 8.13 (1H, s). [M+H] Calc'd for C₁₇H₁₇ClN₂O₂, 317; found, 317.

Preparation 27A: 2-cyclopropyl-4-(trifluoromethyl)-benzonitrile

The title compound was prepared in 71% yield from2-bromo-4-(trifluoromethyl)-benzonitrile according to the generalprocedure for Preparation 19C. [M+H] Calc'd for C₁₁H₈F₃N, 212; found,212.

Preparation 27B: 2-cyclopropyl-4-(trifluoromethyl)-benzylamine

The title compound was prepared in 80% yield from Preparation 27Aaccording to the general procedure for Preparation 26B.

Example 27:3-{[2-cyclopropyl-4-(trifluoromethyl)benzyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 2% yield from Preparation 27B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 0.75-0.79 (2H, m), 0.98-1.03(2H, m), 2.11-2.15 (1H, m), 4.83 (2H, s), 7.33 (1H, s), 7.43 (1H, d,J=8.0 Hz), 7.51 (1H, d, J=8.0 Hz), 7.65 (1H, d, J=5.2 Hz), 7.87 (1H, d,J=4.0 Hz), 8.04-8.08 (2H, m). [M+H] Calc'd for C₁₇H₁₅F₃N₂O₂, 337; found,337.

Example 28: 3-[(naphthalene-1-ylmethyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 66% yield from 1-naphthylmethylamineand 3-fluoroisonicotinic acid according to the procedure for thepreparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 13.39 (br s, 1H),8.25 (s, 1H), 8.15 (d, 1H, J=7.9 Hz), 7.98 (d, 1H, J=7.5 Hz), 7.84-7.89(m, 2H), 7.45-7.62 (m, 5H), 5.03 (s, 2H). [M+H] calc'd for C₁₇H₁₄N₂O₂,279; found 279.

Preparation 29A:1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indole-7-carbonitrile

7-Cyanoindole (1.0 g, 7.0 mmol) was stirred in DMF (10 mL) at 0° C.Sodium hydride (60%, 310 mg, 7.7 mmol) was added, and the reactionstirred 30 min at rt. SEM-chloride was added, and the reaction stirred16 hr. The solution was concentrated in vacuo and purified by silica gelchromatography (10%-40% EtOAc/hexanes) to give 1.5 g (78%) of the titlecompound as a clear oil. ¹H NMR (400 MHz, CDCl₃): δ 7.85 (dd, 1H, J=7.9,0.9 Hz), 7.56 (d, 1H, J=7.5 Hz), 7.26 (d, 1H, J=6.3 Hz), 7.17 (t, 1H,J=7.7 Hz), 6.62 (d, 1H, J=3.3 Hz), 5.79 (s, 2H), 3.58 (t, 2H, J=8.1 Hz),0.92 (t, 2H, J=8.2 Hz), −0.05 (s, 9H). [M+H] calc'd for C₁₅H₂₀N₂OSi,273; found 273.

Preparation 29B:(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-yl)methanamine

Hydrogenation of Preparation 29A (1.5 g, 5.5 mmol) was carried out withRaney nickel in MeOH under a balloon of hydrogen for 16 hr. The reactionwas filtered and concentrated. Purification by silica gel chromatography(1-10% MeOH/DCM) gave 1.02 g (67%) of the title compound as a clear oil.¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, 1H, J=7.4 Hz), 7.08-7.15 (m, 3H),6.51 (d, 1H, J=3.2 Hz), 5.73 (s, 2H), 4.28 (s, 2H), 3.48 (t, 2H, J=8.2Hz), 1.73 (br s, 2H), 0.88 (t, 2H, J=8.2 Hz), −0.05 (s, 9H). [M+H]calc'd for C₁₅H₂₄N₂OSi, 277; found 277.

Preparation 29C: methyl3-{[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 66% yield from Preparation 29B andmethyl-3-bromoisonicotinate according to the procedure for Preparation4A. [M+H] calc'd for C₂₂H₂₉N₃O₃Si, 412; found 412.

Preparation 29D:3-{[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-7-yl)methyl]amino}pyridine-4-carboxylic acid

The title compound was prepared in 85% yield from Preparation 29Caccording to the general hydrolysis procedure outlined for Example 13.¹H NMR (400 MHz, DMSO-d₆): δ 13.53 (br s, 1H), 8.31 (s, 1H), 7.97 (d,1H, J=5.0 Hz), 7.89 (br s, 1H), 7.59-7.71 (m, 3H), 7.11-7.21 (m, 2H),6.61 (d, 1H, J=3.2 Hz), 5.65 (s, 2H), 5.08 (s, 2H), 3.53 (t, 2H, J=8.1Hz), 0.91 (t, 2H, J=8.1 Hz), −0.01 (s, 9H). [M+H] calc'd forC₂₁H₂₇N₃O₃Si, 398; found 398.

Example 29: 3-[(1H-indol-7-ylmethyl)amino]pyridine-4-carboxylic acid

Preparation 29C (200 mg, 0.5 mmol) was stirred in THF (10 mL). TBAF (1N,2.0 mL, 2.0 mmol) was added, and the reaction stirred at 68° C. for 16h. The solution was concentrated and purified by prep-HPLC (5-95%ACN/water with 0.1% formic acid) to give 38 mg (28%) of the titlecompound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.34 (br s,1H), 11.27 (s, 1H), 8.27 (s, 1H), 7.98 (br s, 1H), 7.82 (d, 1H, J=5.0Hz), 7.56 (d, 1H, J=5.0 Hz), 7.48 (d, 1H, J=7.8 Hz), 7.39 (t, 1H, J=2.8Hz), 7.08 (d, 1H, J=7.0 Hz), 6.97 (t, 1H, J=7.5 Hz), 6.47 (dd, 1H,J=2.9, 1.8 Hz), 4.78 (s, 2H). [M+H] calc'd for C₁₅H₁₃N₃O₂, 268; found268.

Preparation 30A: 2-cyclopropyl-3-methyl-benzonitrile

The title compound was prepared in 50% yield from2-bromo-3-methyl-benzonitrile according to the general procedure forPreparation 19C. ¹H NMR (400 MHz, CDCl₃): δ 0.78-0.84 (2H, m), 1.14-1.21(2H, m), 1.89-1.95 (1H, m), 2.47 (3H, s), 7.21 (1H, t, J=10.0 Hz), 7.35(1H, d, J=10.0 Hz), 7.46 (1H, d, J=9.6 Hz).

Preparation 30B: 2-cyclopropyl-3-methyl-benzylamine

The title compound was prepared in 89% yield from Preparation 30Aaccording to the general procedure for Preparation 26B. ¹H NMR (400 MHz,CDCl₃): δ 0.57-0.62 (2H, m), 1.04-1.10 (2H, m), 1.73-1.79 (1H, m), 2.45(3H, s), 4.09 (2H, s), 7.05-7.08 (1H, m), 7.12-7.19 (2H, m).

Example 30: 3-[(2-cyclopropyl-3-methylbenzyl)amino]pyridine-4-carboxylicacid

The title compound was prepared in 17% yield from Preparation 30B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 0.56-0.58 (2H, m), 1.00-1.03(2H, m), 1.78-1.82 (1H, m), 2.36 (3H, s), 4.71 (2H, s), 7.07-7.11 (3H,m), 7.57 (1H, d, J=5.1 Hz), 7.81 (1H, d, J=5.1 Hz), 8.12 (1H, s). [M+H]Calc'd for C₁₇H₁₈N₂O₂, 283; found, 283.

Preparation 30C: methyl3-[(2-cyclopropyl-3-methylbenzyl)amino]pyridine-4-carboxylate

The title compound was prepared in 51% yield from Example 30 accordingto the procedure for Preparation 26C. ¹H NMR (300 MHz, DMSO-d₆): δ0.56-0.58 (2H, m), 1.01-1.05 (2H, m), 1.80-1.85 (1H, m), 2.40 (3H, s),3.87 (3H, s), 4.75 (2H, s), 7.07-7.11 (3H, m), 7.75 (1H, d, J=5.7 Hz),7.907.94 (2H, m), 8.20 (1H, s). [M+H] Calc'd for C₁₇H₁₈N₂O₂, 283; found,283.

Preparation 31A: 4-cyclopropyl-3-cyano-pyridine

The title compound was prepared in 72% yield from4-chloro-3-cyano-pyridine according to the general procedure forPreparation 19C. ¹H NMR (400 MHz, CDCl₃): δ 0.92-0.96 (2H, m), 1.29-1.34(2H, m), 2.26-2.32 (1H, m), 6.77 (1H, t, J=5.6 Hz), 8.58 (1H, d, J=5.6Hz), 8.74 (1H, s).

Preparation 31B: (4-cyclopropylpyridin-3-yl)-methylamine

The title compound was prepared in 91% yield from Preparation 31Aaccording to the general procedure for Preparation 26B.

Example 31:3-{[(4-cyclopropylpyridin-3-yl)-methyl]amino}pyridine-4-carboxylic acid

The title compound was prepared in 8% yield from Preparation 31B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, CD₃OD): δ 1.20-1.23 (2H, m), 1.47-1.50(2H, m), 2.37-2.39 (1H, m), 4.92 (2H, s), 7.53 (1H, d, J=6.4 Hz), 8.06(1H, d, J=5.6 Hz), 8.23 (1H, d, J=5.6 Hz), 8.31 (1H, s), 8.58-8.59 (2H,m). [M+H] Calc'd for C₁₅H₁₅N₃O₂, 270; found, 270.

Example 32: 3-{[3-(trifluoromethyl)benzyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 39% yield from3-trifluoromethyl-benzylamine and 3-fluoroisonicotinic acid according tothe procedure for the preparation of Example 3. ¹H NMR (400 MHz,DMSO-d₆): δ 13.47 (br s, 1H), 8.12 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.74(s, 1H), 7.57-7.69 (m, 4H), 4.67 (s, 2H). [M+H] calc'd for C₁₄H₁₁F₃N₂O₂,297; found 297.

Preparation 32A: methyl3-{[3-(trifluoromethyl)benzyl]amino}pyridine-4-carboxylate

The title compound was prepared in 70% yield from Example 32 accordingto the procedure for Preparation 19B. ¹H NMR (400 MHz, CDCl₃): δ 8.15(s, 1H), 7.88-7.97 (m, 2H), 7.67 (br s, 1H), 7.61 (s, 1H), 7.45-7.57 (m,3H), 4.59 (d, 2H, J=5.9 Hz), 3.92 (s, 3H). [M+H] calc'd forC₁₅H₁₃F₃N₂O₂, 311; found 311.

Example 33A: 2-phenoxy-benzonitrile

To a suspension of 2-fluorobenzonitrile (10.0 g, 82.6 mmol) and phenol(7.7 g, 5.1 mmol) in DMF (80 mL) was added K₂CO₃ (22.8 g, 165 mmol) atrt. The reaction was stirred at 130° C. for 10 hr. The reaction mixturewas diluted with water, extracted with EtAOAc (100 mL×3), washed withbrine (100 mL), dried (Na₂SO₄), and concentrated to give 15.0 g, (93%)of the title compound as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 6.85(1H, d, J=8.4 Hz), 7.07-7.14 (3H, m), 7.22 (1H, t, J=7.2 Hz), 7.40 (2H,t, J=8.0 Hz), 7.47 (1H, td, J=2.0, 8.4 Hz), 7.65 (1H, dd, J=1.2, 8.0Hz).

Preparation 33B: 2-phenoxybenzylamine

The title compound was prepared in 98% yield from Preparation 33Aaccording to the general procedure for Preparation 26B.

Example 33: 3-[(2-phenoxybenzyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 12% yield from Preparation 33B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 4.57 (2H, s), 6.87 (1H, d,J=8.1 Hz), 6.98 (2H, d, J=7.8 Hz), 7.12 (2H, d, J=7.8 Hz), 7.27 (1H, t,J=7.5 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=5.1 Hz), 7.81 (1H, d, J=5.1Hz), 7.95 (1H, br s), 8.18 (1H, s). [M+H] Calc'd for C₁₉H₁₆N₂O₃, 321;found, 321.

Preparation 34A: 2-cyclopropyl-5-methyl-benzonitrile

The title compound was prepared in 75% yield from2-bromo-5-methyl-benzonitrile according to the general procedure forPreparation 19C. ¹H NMR (400 MHz, CDCl₃): δ 0.73-0.77 (2H, m), 1.07-1.12(2H, m), 2.21-2.25 (1H, m), 2.35 (3H, s), 6.83 (1H, d, J=8.0 Hz),7.25-7.28 (1H, m), 7.38 (1H, dd, J=0.8, 1.6 Hz).

Preparation 34B: 2-cyclopropyl-5-methyl-benzylamine

The title compound was prepared in 81% yield from Preparation 34Aaccording to the general procedure for Preparation 26B.

Example 34: 3-[(2-cyclopropyl-5-methylbenzyl)amino]pyridine-4-carboxylicacid

The title compound was prepared in 19% yield from Preparation 34B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 0.59-0.64 (2H, m), 0.86-0.92(2H, m), 1.95-1.99 (1H, m), 2.22 (3H, s), 4.64 (2H, s), 6.93 (1H, d,J=7.8 Hz), 7.01 (1H, d, J=7.8 Hz), 7.09 (1H, s), 7.58 (1H, d, J=5.1 Hz),7.84 (1H, d, J=5.1 Hz), 8.20 (1H, s). [M+H] Calc'd for C₁₇H₁₈N₂O₂, 283;found, 283.

Example 35: 3-{[3-(trifluoromethoxy)benzyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 4% yield from3-trifluoromethoxy-benzylamine and 3-fluoroisonicotinic acid accordingto the procedure for the preparation of Example 3. ¹H NMR (400 MHz,DMSO-d₆): δ 13.47 (br s, 1H), 8.11 (br s, 1H), 7.84 (br s, 1H), 7.59 (s,1H), 7.24-7.51 (m, 4H), 4.64 (s, 2H). [M+H] calc'd for C₁₄H₁₁F₃N₂O₃,313; found 313.

Example 36A: 2-(phenylamino)benzonitrile

To a suspension of 2-bromobenzonitrile (1.5 g, 8.2 mmol), aniline (1.1g, 12.4 mmol), Xantphos (0.7 g, 1.2 mmol) and cesium carbonate (5.4 g,16.5 mmol) in dioxane (50 mL) was added Pd₂dba₃ (375 mg, 0.4 mmol) at rtunder N₂. The reaction was stirred at 90° C. for 8 hr. The reactionmixture was filtered and concentrated. Purification by silica gelchromatography (PE:EtOAc=200:1) gave 1.3 g (81%) of the title compoundas a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 6.36 (1H, br s), 6.86 (1H,td, J=0.9, 7.8 Hz), 7.13-7.18 (4H, m), 7.36-7.41 (3H, m), 7.51 (1H, dd,J=1.8, 7.8 Hz).

Preparation 36B: 2-(phenylamino)benzylamine

The title compound was prepared in 98% yield from Preparation 36Aaccording to the general procedure for Preparation 26B.

Example 36: 3-{[2-(phenylamino)benzyl]amino}pyridine-4-carboxylic acid

The title compound was prepared in 11% yield from Preparation 36B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 4.53 (2H, s), 6.79 (1H, t,J=7.2 Hz), 6.90 (2H, d, J=8.0 Hz), 6.96 (1H, td, J=1.6, 8.0 Hz),7.17-7.23 (4H, m), 7.29 (1H, d, J=7.6 Hz), 7.55 (1H, d, J=6.0 Hz), 7.59(1H, s), 7.81 (1H, d, J=4.8 Hz), 8.08 (1H, s). [M+H] Calc'd forC₁₉H₁₇N₃O₂, 320; found, 320.

Example 37: 3-{[3-(cyclopropylmethoxy)benzyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 7% yield from3-cyclopropylmethoxy-benzylamine hydrochloride and 3-fluoroisonicotinicacid according to the procedure for the preparation of Example 5. ¹H NMR(400 MHz, DMSO-d₆): δ 8.07 (s, 1H), 7.79 (d, 1H, J=5.0 Hz), 7.57 (d, 1H,J=5.0 Hz), 7.23 (t, 1H, J=8.0 Hz), 6.89-6.95 (m, 2H), 6.79 (d, 1H, J=7.6Hz), 4.49 (s, 2H), 3.78 (d, 2H, J=6.9 Hz), 1.15-1.21 (m, 1H), 0.51-0.57(m, 2H), 0.27-0.32 (m, 2H). [M+H] calc'd for C₁₇H₁₈N₂O₃, 299; found 299.

Example 38: 3-[(1-benzofuran-3-ylmethyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 8% yield from(1-benzofuran-3-yl)methylamine hydrochloride and 3-fluoroisonicotinicacid according to the procedure for the preparation of Example 5. ¹H NMR(400 MHz, DMSO-d₆): δ 13.39 (br s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.77(d, 1H, J=5.0 Hz), 7.68 (br s, 1H), 7.57 (d, 1H, J=7.6 Hz), 7.48-7.52(m, 2H), 7.17-7.28 (m, 2H), 4.64 (s, 2H). [M+H] calc'd for C₁₅H₁₂N₂O₃,267; found 267.

Example 39:3-{[(5-methylthiophen-2-yl)methyl]amino}pyridine-4-carboxylic acid

The title compound was prepared in 7% yield from5-methylthiophen-2-ylmethylamine and 3-fluoroisonicotinic acid accordingto the procedure for the preparation of Example 3. ¹H NMR (400 MHz,DMSO-d₆): δ 8.27 (br s, 1H), 7.84 (br s, 1H), 7.57 (d, 1H, J=4.8 Hz),6.87 (d, 1H, 3.2 Hz), 6.65 (d, 1H, J=2.3 Hz), 4.65 (s, 2H), 2.38 (s,3H). [M+H] calc'd for C₁₂H₁₂N₂O₂S, 249; found 249.

Example 40: 3-{[(5-methylfuran-2-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 34% yield from 5-methylfurfurylamineand 3-fluoroisonicotinic acid according to the procedure for thepreparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 13.45 (br s, 1H),8.35 (s, 1H), 7.86 (d, 1H, J=5.0 Hz), 7.77 (br s, 1H), 7.57 (d, 1H,J=5.0 Hz), 6.24 (d, 1H, J=2.9 Hz), 6.00 (d, 1H, J=2.0 Hz), 4.50 (s, 2H),2.23 (s, 3H). [M+H] calc'd for C₁₂H₁₂N₂O₃, 233; found 233.

Preparation 40A: methyl3-{[(5-methylfuran-2-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 71% yield from Example 40 accordingto the procedure for Preparation 19B. ¹H NMR (400 MHz, CDCl₃): δ 8.34(s, 1H), 7.94 (d, 1H, J=5.1 Hz), 7.8 (br s, 1H), 7.63 (dd, 1H, J=5.1,0.3 Hz), 6.15 (d, 1H, J=3.0 Hz), 5.89-5.91 (m, 1H), 4.43 (d, 2H, J=5.7Hz), 3.89 (s, 3H), 2.38 (s, 3H). [M+H] calc'd for C₁₃H₁₄N₂O₃, 247; found247.

Example 41: 3-[(1-benzofuran-2-ylmethyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 3% yield from(1-benzofuran-2-ylmethyl)amine hydrochloride and 3-fluoroisonicotinicacid according to the procedure for the preparation of Example 5. ¹H NMR(400 MHz, DMSO-d₆): δ 13.44 (br s, 1H), 8.39 (s, 1H), 7.97 (br s, 1H),7.87 (d, 1H, J=5.0 Hz), 7.52-7.60 (m, 3H), 7.19-7.29 (m, 2H), 6.81 (s,1H), 4.79 (s, 2H). [M+H] calc'd for C₁₅H₁₂N₂O₃, 269; found 269.

Example 42: 3-[(adamantan-1-ylmethyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 38% yield from1-adamanteanemethylamine and 3-fluoroisonicotinic acid according to theprocedure for the preparation of Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ13.31 (br s, 1H), 8.28 (s, 1H), 7.77 (d, 1H, J=5.0 Hz), 7.54 (d, 1H,J=5.0 Hz), 2.99 (s, 2H), 1.95-2.00 (m, 3H), 1.56-1.72 (m, 12H). [M+H]calc'd for C₁₇H₂₂N₂O₂, 287; found 287.

Preparation 42A: methyl3-[(adamantan-1-ylmethyl)amino]pyridine-4-carboxylate

The title compound was prepared in 42% yield from Example 42 accordingto the procedure for Preparation 19B. ¹H NMR (400 MHz, CDCl₃): δ 8.26(s, 1H), 7.85 (d, 1H, J=5.0 Hz), 7.60 (d, 1H, J=5.0 Hz), 7.55 (br s,1H), 3.90 (s, 3H), 2.97 (d, 2H, J=5.6 Hz), 2.00-2.05 (m, 3H), 1.62-1.74(m, 12H). [M+H] calc'd for C₁₈H₂₄N₂O₂, 301; found 301.

Example 43:3-[(2,3-dihydro-1-benzofuran-2-ylmethyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 18% yield from(2,3-dihyro-1-benzofuran-2-yl) methylamine hydrochloride and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ 13.41 (br s, 1H), 8.29 (s,1H), 7.78 (d, 1H, J=5.0 Hz), 7.75 (br s, 1H), 7.48 (d, 1H, J=5.0 Hz),7.15 (d, 1H, J=7.2 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.75 (t, 1H, J=7.4 Hz),6.67 (d, 1H, J=7.9 Hz), 4.95-4.99 (m, 1H), 3.24-3.64 (m, 3H), 2.88-2.95(m, 1H). [M+H] calc'd for C₁₅H₁₄N₂O₃, 271; found 271.

Example 44:3-[(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]pyridine-4-carboxylicacid

The title compound was prepared in 6% yield from2,3-dihydro-1,4-benzodioxin-2-ylmethylamine and 3-fluoroisonicotinicacid according to the procedure for the preparation of Example 3. ¹H NMR(400 MHz, DMSO-d₆): δ 13.43 (br s, 1H), 8.37 (s, 1H), 7.87 (d, 1H, J=5.0Hz), 7.77 (br s, 1H), 7.57 (d, 1H, J=5.0 Hz), 6.80-6.90 (m, 4H),4.37-4.48 (m, 2H), 4.02-4.07 (m, 1H), 3.55-3.75 (m, 2H). [M+H] calc'dfor C₁₅H₁₄N₂O₄, 287; found 287.

Example 45:3-[(2,3-dihydro-1H-inden-1-ylmethylbenzyl)amino]pyridine-4-carboxylicacid

The title compound was prepared in 19% yield from 1-aminomethylindanehydrochloride and 3-fluoroisonicotinic acid according to the procedurefor the preparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ 13.38 (brs, 1H), 8.35 (s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.55 (d, 1H, J=5.0 Hz),7.35 (t, 1H, J=4.1 Hz), 7.14-7.26 (m, 3H), 3.62-3.67 (m, 1H), 3.36-3.49(m, 2H), 2.69-3.02 (m, 2H), 2.21-2.28 (m, 1H), 1.80-1.89 (m, 1H). [M+H]calc'd for C₁₆H₁₆N₂O₂, 269; found 269.

Preparation 46A: methyl3-[(1,2,3,4-tetrahydronaphthalen-1-yl-methyl)amino]pyridine-4-carboxylate

Methyl 3-bromoisonicotinate (1.34 g, 6.2 mmol)1,2,3,4-tetrahydro-1-naphthalene-methanamine (1.0 g, 6.62 mmol), andcesium carbonate (3.0 g, 9.43 mmol) were combined in dioxane (12 mL)under N₂ in a microwave vial. Pd₂dba₃ (284 mg, 0.31 mmol) and Xantphos(538 mg, 0.93 mmol) were added, and the reaction stirred at 128° C. inthe microwave for 90 min. The reaction was filtered, washing withacetone, and concentrated in vacuo. Purification by silica gelchromatography (20-80% EtOAc/hexanes) gave 826 (45%) of the titlecompound as a light orange solid. ¹H NMR (400 MHz, CDCl₃): δ 8.32 (s,1H), 7.91 (d, 1H, J=5.1 Hz), 7.64 (d, 1H, J=5.0 Hz), 7.59 (s, 1H), 7.24(d, 1H, J=4.9 Hz), 7.11-7.19 (m, 3H), 3.89 (s, 3H), 3.56-3.63 (m, 1H),3.39-3.47 (m, 1H), 3.18-3.21 (s, 1H), 2.78-2.84 (m, 2H), 1.77-1.97 (m,4H). [M+H] calc'd for C₁₈H₂₀N₂O₂, 297; found 297.

Example 46:3-[(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)amino]pyridine-4-carboxylicacid

Preparation 46A (40 mg, 0.13 mmol) was stirred in MeOH (3 mL) with 1NNaOH (1 mL) at 50° C. for 1 hr. The solution was cooled to rt,neutralized with HOAc, and concentrated in vacuo. The residue wasprecipitated with water and the resulting solid was collected byfiltration. The solid was washed with MeOH and dried in vacuo to yield28 mg (74%) of the title compound as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 13.32 (br s, 1H), 8.34 (s, 1H), 7.82 (d, 1H, J=5.0 Hz), 7.56(d, 1H, J=5.0 Hz), 7.31 (t, 1H, J=4.3 Hz), 7.08-7.13 (m, 3H), 3.41-3.60(m, 2H), 3.08-3.11 (m, 1H), 2.70-2.76 (m, 2H), 1.65-1.89 (m, 4H). [M+H]calc'd for C₁₇H₁₈N₂O₂, 283; found 283.

Preparation 47A and Preparation 48A: methyl3-{[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl-methyl]amino}pyridine-4-carboxylate;methyl3-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl-methyl]amino}pyridine-4-carboxylate

Preparation 46A (94 mg) was separated by chiral HPLC (Column: ChiralcelOD-H, 250 mm*4.6 mm 5 μm; Mobile phase: Hex:IPA=80:20; F: 1.0 mL/min; W:230 nm; T=30° C.) to give to give the two enantiomers: 35 mg (33%) ofthe first isomer eluted at 4.93 min, and 35 mg (33%) of the secondisomer eluted at 5.38 min.

Example 47 and Example 48:3-{[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylmethyl]amino}-pyridine-4-carboxylicacid;3-{[(1R)-1,2,3,4-tetrahydronaphthalen-1-ylmethyl]amino}pyridine-4-carboxylicacid

To a solution of the ester from Preparation 46A or 47A (35 mg, 0.12mmol) in THF (5 mL) and water (5 mL) was added lithium hydroxidemonohydrate (10 mg, 0.24 mmol), and the reaction stirred for 3 hr at rt.The solution was concentrated in vacuo to remove THF, and then acidifiedto pH 5 with 0.5 N HCl. The resulting precipitate was collected byfiltration and dried under vacuum to give 20 mg (61%) of the titlecompound as a white solid. NMR and MS for each of the title compoundsmatched Example 46.

Example 49:3-{[(1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 8% yield from1-(1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine hydrochlorideand 3-fluoroisonicotinic acid according to the procedure for thepreparation of Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ 13.24 (br s, 1H),8.31 (s, 1H), 7.78 (d, 1H, J=5.0 Hz), 7.48 (d, 1H, J=5.0 Hz), 7.45 (brs, 1H), 7.42 (d, 1H, J=7.3 Hz), 7.05-7.15 (m, 3H), 3.44-3.57 (m, 2H),2.72 (t, 2H, J=6.4 Hz), 1.59-1.92 (m, 4H), 1.32 (s, 3H). [M+H] calc'dfor C₁₈H₂₀N₂O₂, 297; found 297.

Preparation 50A: 1-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1yl)methanamine

To a solution of 7-fluoro-1-tetralone (2.0 g, 12.2 mmol) and ZnI₂ (20mg) in toluene (20 mL) was added TMS-CN (3.27 mL, 26.1 mmol) at rt. Themixture was heated at 60° C. overnight and then was cooled to rt anddiluted with THF (20 mL). This was slowly added to a solution of lithiumaluminum hydride (930 mg, 24.5 mmol) in THF (10 mL) at rt, and thereaction mixture was heated to 40° C. for 4 hr. The reaction wasquenched with the addition of EtOAc (10 mL) at rt and was stirred for 30min. Water (1 mL) and aqueous 1 N NaOH (1 mL) were added, and themixture stirred 30 min. The mixture was dried (Na₂SO₄), filtered, andconcentrated to give crude intermediate (2.3 g, 97%) as a yellow oil.

To a solution of the intermediate (2.3 g, 11.8 mmol) in toluene (30 mL)was added HCl/dioxane (10 mL, 4.0 M), and the reaction stirred at refluxovernight. The reaction was cooled to rt and concentrated in vacuo.

Hydrogenation of the resulting intermediated was carried out in thepresence of Raney Nickel (750 mg) in 2:1 MeOH/HOAc under 50 psi of H₂for 6 hr. The reaction was filtered through Celite and concentrated invacuo. Purification by silica gel chromatography (5-20% MeOH/DCM with0.5% Et₃N) gave 1.2 g (57%) of the title compound as a white solid.[M+H] calc'd for C₁₁H₁₄FN, 180; found 180. The presence of unreducedmaterial was also detected.

Example 50:3-{[(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 4% yield from Preparation 50A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 13.37 (br s, 1H), 8.39 (s,1H), 7.84 (d, 1H, J=5.0 Hz), 7.73 (br s, 1H), 7.56 (d, 1H, J=5.0 Hz),7.10-7.23 (m, 2H), 6.92-7.00 (m, 1H), 3.43-3.65 (m, 2H), 3.10-3.14 (m,1H), 2.64-2.72 (m, 2H), 1.65-1.87 (m, 4H). [M+H] calc'd for C₁₇H₁₇FN₂O₂,301; found 301.

Example 51:3-{[(7-fluoro-3,4-dihydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was isolated in 4% yield as a side-product in thepreparation of Example 50, due to incomplete reduction in thehydrogenation step for Preparation 50A. ¹H NMR (400 MHz, DMSO-d₆): δ13.35 (br s, 1H), 8.27 (s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.79 (br s, 1H),7.56 (d, 1H, J=5.0 Hz), 7.19-7.23 (m, 2H), 6.97-7.01 (m, 1H), 6.15 (t,1H, J=4. Hz), 4.37 (s, 2H), 2.64-2.69 (m, 2H), 2.23-2.28 (m, 2H). [M+H]calc'd for C₁₇H₁₅FN₂O₂, 299; found 299.

Preparation 52A: 1-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1yl)methanamine

TMS-cyanide (8.52 mL, 68.1 mmol) was added to a solution of5,7-dimethyl-1-tetralone (2.5 g, 14.4 mmol) in toluene (20 mL). A traceamount (˜20 mg) of zinc iodide was added, and the reaction was stirredat 60° C. for 16 hr. The solution was cooled to rt and diluted with THF(10 mL). This was added to a mixture of lithium aluminum hydride (1.09g, 28.7 mmol) in THF (20 mL), and the reaction mixture was heated at 42°C. for 4 hr. The reaction was cooled to rt. EtOAc (5 mL) was slowlyadded, and the reaction stirred 30 min. Water (1 mL) and then 2N NaOH (1mL) were slowly added, and the reaction stirred 1 hr. The reactionmixture was diluted with EtOAc (50 mL), dried (MgSO₄), and filteredthrough Celite.

The crude intermediate was taken up in toluene (30 mL). 4N HCl indioxane (10 mL) was added, and the reaction was heated at reflux under aDean-Stark condenser for 8 hr. The solution was concentrated in vacuo.

Hydrogenation of this crude intermediate was carried out in the presenceof 10% Pd/C in 3:1 MeOH:HOAc under 50 psi of H₂ for 16 hr. The reactionwas filtered through Celite and concentrated in vacuo. Purification bysilica gel chromatography (5%-20% MeOH/DCM with 0.5% Et₃N) gave 1.20 g(44%) of the title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ 6.87 (s, 1H), 6.83 (s, 1H), 2.96-23.02 (m, 2H), 2.82-2.90 (m, 1H),2.38-2.52 (m, 2H), 2.21 (s, 3H), 2.12 (s, 3H), 1.67-1.86 (m, 4H). [M+H]calc'd for C₁₃H₁₉N, 190; found 190.

Example 52:3-{[(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 8% yield from Preparation 52A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 8.35 (s, 1H), 7.83 (d, 1H,J=5.0 Hz), 7.76 (br s, 1H), 7.57 (d, 1H, J=5.0 Hz), 6.93 (s, 1H), 6.82(s, 1H), 3.40-3.53 (m, 2H), 2.99-3.05 (m, 1H), 2.56-2.63 (m, 2H), 2.20(s, 3H), 2.13 (s, 3H), 1.72-1.87 (m, 4H). [M+H] calc'd for C₁₉H₂₂N₂O₂,311; found 311.

Preparation 53A: 7-cyclopropyl-3,4,-dihydronaphthalen-1(2H)-one

The title compound was prepared in 77% yield from 7-bromo-1-tetraloneaccording to the general procedure for Preparation 19C. ¹H NMR (400 MHz,CDCl₃): δ 7.72 (d, 1H, J=2.0 Hz), 7.21 (dd, 1H, J=7.9, 2.0 Hz), 7.13 (d,1H, J=7.9 Hz), 2.91 9t, 2H, J=6.1 Hz), 2.63 (t, 2H, J=6.1 Hz), 2.09-2.15(m, 2H), 1.87-1.93 (m, 1H), 0.93-0.99 (m, 2H), 0.69-0.73 (m, 2H). [M+H]calc'd for C₁₃H₁₄O, 187; found 187.

Preparation 53B: 1-(7-cyclopropyl-1,2,3,4-tetrahydronaphthalen-1yl)methanamine

The title compound was prepared in 47% yield from Preparation 53Aaccording to the general procedure for Preparation 52A. ¹H NMR (400 MHz,CDCl₃): δ 9.22 (br s, 2H), 6.94-6.98 (m, 2H), 6.80 (d, 1H, J=7.8 Hz),3.01-3.22 (m, 3H), 268-2.72 (m, 2H), 1.76-1.91 (m, 5H), 0.88-0.93 (m,2H), 0.62-0.66 (m, 2H). [M+H] calc'd for C₁₄H₁₉N, 202; found 202.

Example 53:3-{[(7-cyclopropyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

3-Fluoroisonicotinic acid (295 mg, 2.09 mmol), Preparation 53B (420 mg,2.09 mmol) and DIEA (364 μL, 2.09 mmol) were combined in DMA (4 mL) andheated at 168° C. in the microwave for 80 min. The reaction wasconcentrated and purified by prep-HPLC (35-80% ACN/water with 0.1%formic acid) to give 32 mg (5%) of the title compound as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.35 (s, 1H), 7.83 (d, 1H, J=5.0Hz), 7.79 (br s, 1H), 7.47 (d, 1H, J=5.0 Hz), 6.93-6.98 (m, 2H), 6.81(dd, 1H, J=7.8, 1.4 Hz), 3.39-3.69 (m, 2H), 3.03-3.06 (m, 1H), 2.63-2.69(m, 2H), 1.63-1.86 (m, 5H), 0.84-0.88 (m, 2H), 0.57-0.62 (m, 2H). [M+H]calc'd for C₂₀H₂₂N₂O₂, 323; found 323.

Preparation 54A:1-(5-fluoro-1,2,3,4-tetrahydronaphthalen-1yl)methanamine

The title compound was prepared in 37% overall yield from5-fluoro-1-tetralone according to the procedure for Preparation 50A,except the reduction step ran for 16 hr instead of 6 hr. [M+H] calc'dfor C₁₁H₁₄FN, 180; found 180.

Example 54:3-{[(5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 6% yield from Preparation 54A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 53. ¹H NMR (400 MHz, DMSO-d₆): δ 8.32 (s, 1H), 7.89 (br s,1H), 8.82 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.15-7.18 (m, 2H),6.95-7.00 (m, 1H), 3.42-3.61 (m, 2H), 3.12-3.16 (m, 1H), 2.54-2.75 (m,2H), 1.69-1.88 (m, 4H). [M+H] calc'd for C₁₇H₁₇FN₂O₂, 301; found 301.

Example 55:3-{[(5-fluoro-1-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was isolated in 2% yield as a side-product from thepreparation of Example 54. ¹H NMR (400 MHz, DMSO-d₆): δ 8.12-8.31 (m,2H), 7.47-7.71 (m, 2H), 7.17-7.22 (m, 1H), 6.98-7.03 (m, 1H), 3.35-3.48(m, 2H), 2.99-3.14 (m, 1H), 2.60-2.74 (m, 2H), 2.08 (br s, 1H),1.73-1.85 (m, 4H). [M+H] calc'd for C₁₇H₁₇FN₂O₃, 317; found 317.

Preparation 56A: methyl3-{[(5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

To a suspension of Preparation 54A (480 mg, 2.7 mmol) in DMA (5 mL) wasadded methyl 3-fluoroisonicotinate at rt. The reaction mixture wasstirred at 170° C. for 1 hr in a microwave. Concentration in vacuofollowed by purification by silica gel chromatography gave 395 mg (47%)of the title compound as a yellow gum. [M+H] calc'd for C₁₈H₁₉FN₂O₂,315; found 315.

Preparation 56B and Preparation 57B: methyl3-({[(1S)-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;methyl3-({[(1R)-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 56A (395 mg) was separated by chiral HPLC (Column: ChiralcelOJ-H, 250 mm*4.6 mm 5 μm; Mobile phase: Hex:IPA=80:20; F: 1.0 mL/min; W:230 nm; T=30° C.) to give to give the two enantiomers: 110 mg (27%) ofthe first isomer eluted at 4.95 min, and 126 mg (31%) of the secondisomer eluted at 5.39 min.

Example 56 and Example 57:3-({[(1S)-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}-amino)pyridine-4-carboxylicacid;3-({[(1R)-5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl]-methyl}amino)pyridine-4-carboxylicacid

To a solution of Preparation 56B (110 mg, 0.35 mmol) in THF (5 mL) andwater (5 mL) was added lithium hydroxide monohydrate (30 mg, 0.7 mmol),and the reaction stirred for 16 h at rt. The solution was concentratedin vacuo to remove THF, and then acidified to pH 3 with 1.0 N HCl. Theresulting precipitate was collected by filtration and dried under vacuumto give 88 mg (83%) of Example 56 as a white solid. Example 57 wasprepared in 88% yield by the same method. NMR and MS for each of thetitle compounds matched Example 54.

Example 58:3-[(3,4-dihydro-2H-chromen-4-ylmethyl)amino]pyridine-4-carboxylic acid

The title compound was prepared in 13% yield from1-(3,4-dihydro-2H-chromen-4-yl) methanamine and 3-fluoroisonicotinicacid according to the procedure for the preparation of Example 53. ¹HNMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 7.78 (d, 1H, J=5.0 Hz), 7.74 (brs, 1H), 7.50 (d, 1H, J=5.0 Hz), 7.23 (d, 1H, J=7.4 Hz), 7.04 (t, 1H,J=7.1 Hz), 6.78 (t, 1H, J=7.3 Hz), 6.69 (d, 1H, J=8.0 Hz), 4.06-4.17 (m,2H), 3.59-3.65 (m, 1H), 3.41-3.47 (m, 1H), 3.04-3.09 (m, 1H), 1.79-1.96(m, 2H). [M+H] calc'd for C₁₆H₁₆N₂O₃, 285; found 285.

Example 59:3-{[(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 17% yield from1-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ 13.36 (br s, 1H), 8.37 (s,1H), 7.83 (d, 1H, J=5.0 Hz), 7.59 (br s, 1H), 7.55 (d, 1H, J=5.0 Hz),7.38 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=6.8 Hz), 7.07-7.19 (m, 2H),3.47-3.58 (m, 2H), 3.07-3.11 (m, 1H), 1.77-1.90 (m, 3H), 1.51-1.57 (m,1H), 1.31 (s, 3H), 1.21 (s, 3H). [M+H] calc'd for C₁₉H₂₂N₂O₂, 311; found311.

Preparation 60A: 1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1yl)methanamine, hydrochloride

TMS-cyanide (8.52 mL, 68.1 mmol) was added to a solution of6-methoxy-1-tetralone (6.0 g, 34 mmol) in toluene (50 mL). A traceamount (˜20 mg) of zinc iodide was added, and the reaction was stirredat 60° C. for 16 hr. The solution was cooled to rt and diluted with THF(30 mL). This was added to a mixture of lithium aluminum hydride (2.58g) in THF (50 mL), and the reaction mixture was heated at 42° C. for 2hr. The reaction was cooled to rt. EtOAc (10 mL) was slowly added, andthe reaction stirred 30 min. Water (2 mL) and then 5N NaOH (1 mL) wereslowly added, and the reaction stirred 1 hr. The reaction mixture wasdiluted with EtOAc (100 mL), dried (MgSO₄), and filtered through Celite.Purification by silica gel chromatography (10%-20% MeOH/DCM) gave 4.82 gof 1-(aminomethyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol as aclear oil.

The intermediate was taken up in toluene (60 mL). 4N HCl in dioxane (20mL) was added, and the reaction was heated at reflux under a Dean-Starkcondenser for 2 hr. The solution was concentrated in vacuo andprecipitated from cold EtOAc. The solid was collected by filtration togive 3.76 g of 1-(6-methoxy-3,4-dihydronaphthalen-1yl)methanamine. ¹HNMR (400 MHz, DMSO-d₆): δ 8.30 (br s, 3H), 7.22 (d, 1H, J=8.4 Hz),6.76-6.83 (m, 2H), 6.05 (t, 1H, J=4.5 Hz), 3.82 (br s, 2H), 3.76 (s,3H), 2.69 (t, 2H, J=7.9 Hz), 2.22-2.28 (m, 2H). [M+H] calc'd forC₁₂H₁₅NO, 190; found 190.

Hydrogenation of 1-(6-methoxy-3,4-dihydronaphthalen-1yl)methanamine wascarried out in the presence of 10% Pd/C in 3:1 MeOH:HOAc under 50 psi ofH₂ for 16 hr. The reaction was filtered through Celite and concentratedin vacuo. Precipitation from EtOAc and collection by filtration gave 3.0g (39%) of the title compound as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 7.88 (br s, 3H), 7.16 (d, 1H, J=8.5 Hz), 6.73 (dd, 1H,J=8.4, 2.6 Hz), 6.64 (d, 1H, J=2.4 Hz), 3.70 (s, 3H), 2.81-3.09 (m, 3H),2.63-2.70 (m, 2H), 1.61-1.87 (m, 4H). [M+H] calc'd for C₁₂H₁₇NO, 192;found 192.

Example 60:3-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 15% yield from Preparation 60A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.35 (s, 1H), 7.83 (d, 1H,J=5.0 Hz), 7.65 (br s, 1H), 7.56 (d, 1H, J=5.0 Hz), 7.21 (d, 1H, J=8.5Hz), 6.70 (dd, 1H, J=8.5, 2.6 Hz), 6.65 (d, 1H, J=2.4 Hz), 3.70 (s, 3H),3.38-3.56 (m, 2H), 3.02-3.06 (m, 1H), 2.67-2.74 (m, 2H), 1.62-1.84 (m,4H). [M+H] calc'd for C₁₈H₂₀N₂O₃, 313; found 313.

Preparation 61A: methyl3-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

Methyl 3-bromoisonicotinate (930 mg, 4.3 mmol), Preparation 60A (980 mg,4.3 mmol), and cesium carbonate (3.5 g, 10.8 mmol) were combined indioxane (12 mL) under N₂ in a microwave vial. Pd₂dba₃ (197 mg, 0.22mmol) and Xantphos (373 mg, 0.65 mmol) were added, and the reactionstirred at 128° C. in the microwave for 1 hr. As there was very littleconversion by HPLC at this point, the reaction was heated an additional2 hr at 148° C. The reaction was filtered, washing with acetone, andconcentrated in vacuo. Purification by silica gel chromatography (20-80%EtOAc/hexanes) gave 256 (18%) of the title compound light yellow oil. ¹HNMR (400 MHz, CDCl₃): δ 8.32 (s, 1H), 7.91 (d, 1H, J=5.2 Hz), 7.62 (dd,1H, J=5.2, 0.5 Hz), 7.56 (br s, 1H), 7.16 (d, 1H, J=8.5 Hz), 6.74 (dd,1H, J=8.4, 2.7 Hz), 6.65 (d, 1H, J=2.7 Hz), 3.89 (s, 3H), 3.78 (s, 3H),3.52-3.58 (m, 1H), 3.37-3.43 (m, 1H), 3.11-3.15 (s, 1H), 2.77-2.82 (m,2H), 1.76-1.95 (m, 4H). [M+H] calc'd for C₁₉H₂₂N₂O₃, 327; found 327.

Preparation 61B and Preparation 62B: methyl3-({[(1S)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;methyl3-({[(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 61A (240 mg) was separated by chiral HPLC (Column: ChiralcelOJ-H, 250 mm*4.6 mm 5 μm; Mobile phase: Hex:IPA=80:20; F: 1.0 mL/min; W:230 nm; T=30° C.) to give to give the two enantiomers: 60 mg (25%) ofthe first isomer eluted at 8.66 and 60 mg (25%) of the second isomereluted at 10.59 min.

Example 61 and Example 62:3-({[(1S)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}-amino)pyridine-4-carboxylicacid;3-({[(1R)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-methyl}amino)pyridine-4-carboxylicacid

Hydrolysis of each of the pure enantiomers (Preparation 61B andPreparation 62B) were carried out as follows: To the ester (60 mg, 0.18mmol) in THF (5 mL) and water (5 mL) was added lithium hydroxidemonohydrate (15 mg, 0.36 mmol), and the reaction stirred for 3 h at rt.The solution was concentrated in vacuo to remove THF, and then acidifiedto pH 5 with 0.5 N HCl. The resulting precipitate was collected byfiltration and dried under vacuum to give 50 mg (89%) of the titlecompound as a yellow solid. NMR and MS for each of the title compoundsmatched Example 60.

Preparation 63A: 1-(6-methyl-3,4-dihydro-2H-chromen-4-yl)methanamine

To a solution of 6-methyl-4-chromanone (2.0 g, 12.3 mmol), ZnI₂ (20 mg)in toluene (20 mL) was added TMS-CN (3.3 mL, 24.7 mmol) at rt. Thesolution was heated at 60° C. overnight. The reaction was cooled to rtand diluted with THF (10 mL), and then it was added dropwise to asolution of lithium aluminum hydride (10.3 mL, 2.4 M, 24.7 mmol) at rt.The reaction mixture was heated to 40° C. for 3 hr, and then cooled tort. EtOAc (10 mL) was added at rt and the reaction stirred for 30 min.Water (2 mL) was added, and then the mixture was dried (Na₂SO₄),filtered, and concentrated to give 2.3 g (95%) of the crude intermediateas a yellow oil.

To a solution of the intermediate (1.5 g, 7.8 mmol) in toluene (20 mL)was added 4N HCl/dioxane (10 mL), and the reaction stirred at refluxovernight. The solution was cooled to 0° C. and filtered to give1-(6-methyl-2H-chromen-4-yl)methanamine hydrochloride (800 mg, 49%) as ayellow solid. ¹H NMR (300 MHz, CD₃OD): δ 2.32 (3H, s), 3.99 (2H, s),4.76 (2H, d, J=3.0 Hz), 6.01 (1H, t, J=3.0 Hz), 6.75 (1H, d, J=6.3 Hz),7.04 (1H, d, J=6.3 Hz), 7.08 (1H, s).

To a solution of 1-(6-methyl-2H-chromen-4-yl)methanamine hydrochloride(700 mg, 3.3 mmol) in MeOH (20 mL) and AcOH (2 mL) under N₂ was added10% Pd/C (70 mg) at rt. The suspension was stirred at rt overnight under50 psi of H₂. The reaction was filtered and concentrated. The residuewas dissolved in EtOAc and washed with sat. Na₂CO₃, and the organicswere concentrated to give 400 mg (68%) of the title compound as a yellowoil. ¹H NMR (300 MHz, CDCl₃): δ 1.98-2.09 (2H, m), 2.28 (3H, s),2.80-2.83 (1H, m), 2.88-2.96 (1H, m), 3.09 (1H, dd, J=4.5, 12.6 Hz),4.17 (2H, t, J=6.3 Hz), 6.73 (1H, d, J=8.4 Hz), 6.91-6.97 (2H, m).

Example 63:3-{[(6-methyl-3,4-dihydro-2H-chromen-4-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 15% yield from Preparation 63A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 1.86-1.90 (1H, m), 1.94-1.98(1H, m), 2.20 (3H, s), 3.07-3.09 (1H, m), 3.47-3.51 (1H, m), 3.66-3.70(1H, m), 4.13-4.16 (2H, m), 6.65 (1H, d, J=8.4 Hz), 6.90 (1H, t, J=8.4Hz), 7.10 (1H, s), 7.59 (1H, d, J=4.8 Hz), 7.86 (1H, d, J=4.8 Hz), 8.43(1H, s). [M+H] Calc'd for C₁₇H₁₈N₂O₃, 299; found, 299.

Preparation 64A:1-[6-(propan-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1yl]methanamine,hydrochloride

The title compound was prepared in 32% yield from6-(propan-2yloxy)-1-tetralone according to the general procedure forPreparation 60A. ¹H NMR (400 MHz, DMSO-d₆): δ 7.49 (br s, 3H), 7.13 (d,1H, J=8.6 H), 6.70 (dd, 1H, J=8.4, 2.6 Hz), 6.61 (d, 1H, J=2.4 Hz),4.51-4.58 (m, 1H), 2.99-3.08 (m, 2H), 2.82-2.89 (m, 1H), 2.63-2.69 (m,2H), 1.62-1.82 (m, 4H), 1.23 (d, 6H, J=6.0 Hz). [M+H] calc'd forC₁₄H₂₁NO, 220; found 220.

Example 64:3-({[(6-(propan-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid

The title compound was prepared in 6% yield from Preparation 64A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 5. ¹H NMR (400 MHz, MeOD): δ 8.14 (s, 1H), 7.84 (d, 1H, J=5.0Hz), 7.78 (br s, 1H), 7.14 (d, 1H, J=8.5 Hz), 6.61-6.68 (m, 2H),4.49-4.56 (m, 1H), 3.40-3.57 (m, 2H), 3.07-3.13 (m, 1H), 2.72-2.81 (m,2H), 1.85-1.94 (m, 3H), 1.71-1.78 (m, 1H), 1.27 (dd, 6H, J=6.0, 1.2 Hz).[M+H] calc'd for C₂₀H₂₄N₂O₃, 341; found 341.

Preparation 65A: 1-(6-fluoro-3,4-dihydro-2H-chromen-4-yl)methanamine

To a solution of 6-fluoro-4-chromanone (2.5 g, 15 mmol) and ZnI₂ (20 mg)in toluene (30 mL) was added TMS-CN (3.0 g, 30.1 mmol) at rt. Themixture was heated at 60° C. overnight and then was cooled to rt anddiluted with THF (20 mL). A solution of lithium aluminum hydride in THF(12.6 mL, 2.4 M, 30.1 mmol) was added dropwise at rt, and the reactionmixture was heated to 40° C. for 4 hr. The reaction was quenched withthe addition of EtOAc (10 mL) at rt and was stirred for 30 min. Water (1mL) and aqueous 1 N NaOH (1 mL) were added, and the mixture was dried(Na₂SO₄), filtered, and concentrated to give crude intermediate (2.3 g,80%) as a yellow oil.

To a solution of the intermediate (2.3 g, 12 mmol) in toluene (50 mL)was added 4N HCl/dioxane (20 mL), and the reaction stirred at reflux for4 hr. The reaction was cooled to rt and filtered to give 1.36 g (63%) of1-(6-fluoro-2H-chromen-4-yl)methanamine hydrochloride as a white solid.¹H NMR (300 MHz, CD₃OD): δ 3.97 (2H, s), 4.78-4.80 (2H, m), 6.10 (1H, brs), 6.82-6.87 (1H, m), 6.92-6.96 (1H, m), 7.05-7.09 (1H, m).

To a solution of 1-(6-fluoro-2H-chromen-4-yl)methanamine hydrochloride(1.36 g, 7.6 mmol) in MeOH (20 mL) and AcOH (10 mL) was added RaneyNickel (760 mg) at rt. The suspension was stirred at rt overnight under50 psi of H₂. The reaction mixture was filtered and concentrated. Theresidue was dissolved in DCM and washed with sat. NaHCO₃, dried(Na₂SO₄), and concentrated to give 490 mg (36%) of the title compound asa green oil. [M+H] calc'd for C₁₀H₁₂FNO, 182; found 182.

Example 65:3-{[(6-fluoro-3,4-dihydro-2H-chromen-4-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 7% yield from Preparation 65A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 1.17-1.98 (2H, m), 3.12-3.25(1H, m), 3.38-3.43 (1H, m), 3.70-3.76 (1H, m), 4.12-4.19 (2H, m),6.75-6.80 (1H, m), 6.91-6.97 (1H, m), 7.17-7.22 (1H, dd, J=3.0 Hz), 7.57(1H, d, J=4.8 Hz), 7.84 (1H, d, J=5.1 Hz), 8.43 (1H, s). [M+H] Calc'dfor C₁₆H₁₅FN₂O₃, 302; found, 302.

Preparation 66A: 1-(7-chloro-3,4-dihydro-2H-chromen-4-yl)methanamine,hydrochloride

To a solution of 7-chloro-4-chromanone (5.0 g, 27.4 mmol) and ZnI₂ (30mg) in toluene (50 mL) was added TMS-CN (6.85 mL, 54.8 mmol) at rt. Themixture was heated at 60° C. overnight and then was cooled to rt anddiluted with THF (40 mL). This was slowly added to a solution of lithiumaluminum hydride (2.08 g, 54.8 mmol) in THF (20 mL) at rt, and thereaction mixture was heated to 42° C. for 4 hr. The reaction wasquenched with the addition of EtOAc (10 mL) at rt and was stirred for 30min. Water (2 mL) and aqueous 1 N NaOH (1 mL) were added, and themixture stirred 30 min. The mixture was dried (MgSO₄), filtered, andconcentrated to give crude intermediate (4.8 g, 82%) as a yellow oil.

To a solution of the intermediate (4.8 g, 22.5 mmol) in toluene (60 mL)was added 4N HCl/dioxane (20 mL), and the reaction stirred at reflux 4hr. The reaction was cooled to rt and concentrated in vacuo. Theresulting oily solid was taken up in EtOAc, sonicated, and the solidcollected by filtration to give 2.2 g (50%) of1-(7-chloro-2H-chromen-4-yl)methanamine hydrochloride as white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 8.37 (br s, 3H), 7.37 (d, 1H, J=2.5 Hz), 7.23(dd, 1H, J=8.6, 2.5 Hz), 6.85 (d, 1H, J=8.6 Hz), 6.10 (s, 1H), 4.80 (t,2H, J=1.8 Hz), 3.87 (s, 2H). [M+H] calc'd for C₁₀H₁₀ClNO, 196; found196.

Hydrogenation of 1-(7-chloro-2H-chromen-4-yl)methanamine hydrochloride(500 mg, 2.6 mmol) was carried out in the presence of Raney Nickel (300mg) in 2:1 MeOH/HOAc under 50 psi of H₂ for 16 hr at 30° C. The reactionwas filtered through Celite and concentrated in vacuo. Precipitationfrom EtOAc and filtration gave 280 mg (56%) of the title compound as awhite solid. [M+H] calc'd for C₁₀H₁₂ClNO, 198; found 198.

Example 66:3-{[(7-chloro-3,4-dihydro-2H-chromen-4-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 6% yield from Preparation 66A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ 13.38 (br s, 1H), 8.46 (s,1H), 7.85 (d, 1H, J=5.0 Hz), 7.68 (br s, 1H), 7.57 (d, 1H, J=5.0 Hz),7.38 (d, 1H, J=2.5 Hz), 7.13 (dd, 1H, J=8.7, 2.6 Hz), 6.79 (d, 1H, J=8.7Hz), 4.14-4.25 (m, 2H), 3.80-3.76 (m, 1H), 3.49-3.56 (m, 1H), 3.13-3.18(m, 1H), 1.83-2.02 (m, 2H). [M+H] calc'd for C₁₆H₁₅ClN₂O₃, 319; found319.

Preparation 67A: 1-(6-chloro-1,2,3,4-tetrahydronaphthalen-1yl)methanamine, hydrochloride

The title compound was prepared in 55% overall yield from6-chloro-1-tetralone according to the procedure for Preparation 66A;however, the product was impure and contained significant amounts ofover-reduced (de-chlorinated) material, as well as un-reduced(dihydronaphthalene) material. [M+H] calc'd for C₁₀H₁₂ClNO, 198; found198.

Example 67:3-{[(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 1% yield from Preparation 67A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 5. ¹H NMR (400 MHz, MeOD): 8.08 (s, 1H), 7.77-7.80 (m, 2H),7.09-7.22 (m, 3H), 3.39-3.54 (m, 2H), 3.12-3.17 (m, 1H), 2.74-2.80 (m,2H), 1.77-1.97 (m, 4H). [M+H] calc'd for C₁₇H₁₇ClN₂O₂, 317; found 317.

Example 68:3-{[(6-chloro-1-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was isolated in <1% yield from the preparation ofExample 67. ¹H NMR (400 MHz, DMSO-d₆): δ 13.30 (br s, 1H), 8.26 (s, 1H),7.84 (br s, 1H), 7.77 (d, 1H, J=5.0 Hz), 7.61 (d, 1H, J=8.4 Hz), 7.52(d, 1H, J=5.0 Hz), 7.16-7.23 (m, 2H), 5.41 (s, 1H), 3.35-3.55 (m, 2H),2.73-2.76 (m, 2H), 2.00-2.05 (m, 1H), 1.74-1.82 (m, 3H). [M+H] calc'dfor C₁₇H₁₇ClN₂O₃, 333; found 333.

Preparation 69A: 1-(7-bromo-2H-chromen-4-yl)methanamine

TMS-cyanide (2.2 mL, 17.6 mmol) was added to a solution of7-bromochroman-4-one (2.0 g, 8.8 mmol) in toluene (20 mL). Zinc iodide(20 mg) was added, and the reaction was stirred at 60° C. for 16 hr. Thesolution was cooled to rt and diluted with THF (10 mL). This was addedto a mixture of lithium aluminum hydride (670 mg, 17.6 mmol) in THF (20mL), and the reaction mixture was heated at 42° C. for 2 hr. Thereaction was cooled to rt. EtOAc (5 mL) was slowly added, and thereaction stirred 30 min. Water (1 mL) and then 5N NaOH (1 mL) wereslowly added, and the reaction stirred 1 hr. The reaction mixture wasdiluted with EtOAc (30 mL), dried (MgSO₄), filtered through Celite, andconcentrated to give 1.8 g (79%) yellow oil.

The intermediate was taken up in toluene (20 mL). 4N HCl in dioxane (10mL) was added, and the reaction was heated at reflux under a Dean-Starkcondenser for 2 hr. The solution was concentrated in vacuo and taken upin EtOAc. The solid was collected by filtration, and was then dissolvedin sat. NaHCO₃ and extracted (3×) with EtOAc. Organics were dried(Na₂SO₄) and concentrated to give 900 mg (54%) of the title compound asa yellow oil. ¹H NMR (300 MHz, CD₃OD): δ 3.98 (2H, s), 4.84-4.87 (2H,m), 6.06 (1H, t, J=3.6 Hz), 7.01 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=1.8,8.4 Hz), 7.18 (1H, d, J=8.4 Hz).

Preparation 69B: tert-butyl [(7-bromo-2H-chromen-4-yl)methyl]carbamate

Preparation 69A (900 mg, 3.75 mmol) was dissolved in DCM (60 mL). DIEA(1.65 mL, 9.5 mmol) and then di-tert-butyl dicarbonate (0.99 g, 4.5mmol) were added, and the reaction stirred at rt for 2 hr. The solutionwas concentrated and purified by silica gel chromatography (20-80%EtOAc/hexanes to give 886 mg (69%) of the title compound as a yellowfoam. ¹H NMR (400 MHz, CDCl₃): δ 6.97-7.03 (m, 3H), 5.72-5.75 (m, 1H),4.76-4.79 (m, 2H), 4.67 (br s, 1H), 4.08-4.15 (m, 2H), 1.45 (s, 9H).[M+H] calc'd for C₁₅H₁₈BrNO₃, 340, 342; found 340, 342.

Preparation 69C: tert-butyl [(7-phenyl-2H-chromen-4-yl)methyl]carbamate

Preparation 69B (820 mg, 2.41 mmol), phenylboronic acid (353 mg, 2.89mmol), and tetrakis(triphenylphosphine)palladium(0) (417 mg, 0.36 mmol)were combined in dioxane (4 mL) with saturated NaHCO₃ (0.5 mL) under N₂.The reaction was heated at 122° C. in a microwave for 1 hr. The reactionwas diluted with DCM, dried (MgSO₄), and concentrated in vacuo.Purification by silica gel chromatography (10-80% EtOAc/hexanes) gave508 mg (63%) of the title compound as a yellow oil, which slowlysolidified overnight. [M+H] calc'd for C₂₁H₂₃NO₃, 338; found 338.

Preparation 69D: 1-(7-phenyl-3,4-dihydro-2H-chromen-4-yl)methanamine

Preparation 69C (508 mg, 1.5 mmol) was stirred in 50% TFA/DCM (6 mL) for1 hr. The solution was concentrated in vacuo. Hydrogenation was carriedout in the presence of 10% Pd/C in 3:1 MeOH:HOAc under 50 psi of H₂ for16 hr. The reaction was filtered through Celite and concentrated invacuo. Purification by silica gel chromatography (5-15% MeOH/DCM) gave258 mg (72%) of the title compound as a light yellow oil. ¹H NMR (400MHz, MeOD): δ 7.40-7.52 (m, 2H), 7.25-7.33 (m, 2H), 7.16-7.23 (m, 2H),7.07-7.11 (m, 1H), 6.98 (d, 1H, J=1.6 Hz), 4.11-4.17 (m, 2H), 3.12-3.17(m, 1H), 3.03-3.09 (m, 2H), 2.05-2.14 (m, 1H), 1.91-1.98 (m, 1H). [M+H]calc'd for C₁₆H₁₇NO, 240; found 240.

Example 69:3-{[(7-phenyl-3,4-dihydro-2H-chromen-4-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 12% yield from Preparation 69D and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 53. ¹H NMR (400 MHz, DMSO-d₆): δ 13.38 (br s, 1H), 8.45 (s,1H), 7.86 (d, 1H, J=5.0 Hz), 7.76 (br s, 1H), 7.57-7.64 (m, 3H),7.36-7.46 (m, 4H), 7.16 (dd, 1H, J=8.0, 1.8 Hz), 7.05 (d, 1H, J=1.8 Hz),4.18-4.29 (m, 2H), 3.73-3.77 (m, 1H), 3.52-3.59 (m, 1H), 3.18-3.21 (m,1H), 1.89-2.07 (m, 2H). [M+H] calc'd for C₂₂H₂₀N₂O₃, 361; found 361.

Preparation 70A: 1-(7-fluoro-3,4-dihydro-2H-chromen-4-yl)methanamine

The title compound was prepared in 45% overall yield from7-fluoro-4-chromanone according to the procedure for Preparation 65A.[M+H] calc'd for C₁₀H₁₂FNO, 182; found 182.

Example 70:3-{[(7-fluoro-3,4-dihydro-2H-chromen-4-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 5% yield from Preparation 70A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 1.89-1.99 (2H, m), 3.10-3.15(1H, m), 3.47-3.55 (1H, m), 3.65-3.71 (1H, m), 4.17-4.23 (2H, m),6.60-6.72 (2H, m), 7.31-7.36 (1H, m), 7.59 (1H, d, J=5.1 Hz), 7.85 (1H,d, J=5.1 Hz), 8.42 (1H, s). [M+H] Calc'd for C₁₆H₁₅FN₂O₃, 302; found,302.

Preparation 71A: 1-(8-fluoro-3,4-dihydro-2H-chromen-4-yl)methanamine

The title compound was prepared in 24% overall yield from8-fluoro-4-chromanone according to the procedure for Preparation 65A.[M+H] calc'd for C₁₀H₁₂FNO, 182; found 182.

Example 71:3-{[(8-fluoro-3,4-dihydro-2H-chromen-4-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 7% yield from Preparation 71A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 1.88-2.04 (2H, m), 3.19-3.23(1H, m), 3.53-3.60 (1H, m), 3.69-3.75 (1H, m), 4.21-4.28 (2H, m),6.79-6.86 (1H, m), 7.01-7.08 (1H, m), 7.13 (1H, d, J=3.6 Hz), 7.75 (1H,d, J=5.1 Hz), 7.92 (1H, s), 8.48 (1H, s). [M+H] Calc'd for C₁₆H₁₅FN₂O₃,302; found, 302.

Preparation 72A: 1-(7-chloro-1,2,3,4-tetrahydronaphthalen-1yl)methanamine, hydrochloride

The title compound was prepared in 25% overall yield from7-chloro-1-tetralone according to the procedure for Preparation 66A;however, the product was impure and contained significant amounts ofover-reduced (de-chlorinated) material, as well as un-reduced(dihydronaphthalene) material. [M+H] calc'd for C₁₀H₁₂ClNO, 198; found198.

Example 72:3-{[(7-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 1% yield from Preparation 72A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 5. ¹H NMR (400 MHz, MeOD): δ 8.15 (s, 1H), 7.76-7.82 (m, 2H),7.26 (s, 1H), 7.06-7.10 (m, 2H), 3.43-3.60 (m, 2H), 3.12-3.16 (m, 1H),2.74-2.83 (m, 2H), 1.76-1.99 (m, 4H). [M+H] calc'd for C₁₇H₁₇ClN₂O₂,317; found 317.

Preparation 73A: 7-phenyl-3,4-dihydronaphthalen-1(2H)-one

The title compound was prepared in 79% yield from 6-bromo-chroman-4-oneaccording to the general procedure for Preparation 69C. [M+H] calc'd forC₁₆H₁₄O, 223; found 223.

Preparation 73B:1-(7-phenyl-1,2,3,4-tetrahydronaphthalen-1yl)methanamine, hydrochloride

The title compound was prepared in 42% yield from Preparation 73Aaccording to the general procedure for Preparation 60A. ¹H NMR (400 MHz,MeOD): δ 7.61 (dd, 2H, J=8.1, 1.2 Hz), 7.53 (d, 1H, J=1.7 Hz), 7.37-7.42(m, 3H), 7.29-7.32 (m, 1H), 7.15 (d, 1H, J=8.0 Hz), 3.27-3.37 (m, 2H),3.11-3.17 (m, 1H), 2.76-2.82 (m, 2H), 1.78-1.98 (m, 4H). [M+H] calc'dfor C₁₇H₁₉N, 238; found 238.

Example 73:3-{[(7-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 7% yield from Preparation 73B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ 13.38 (br s, 1H), 8.42 (s,1H), 7.83 (d, 1H, J=5.0 Hz), 7.76 (br s, 1H), 7.63 (d, 2H, J=7.2 Hz),7.57 (d, 1H, J=5.0 Hz), 7.56 (s, 1H), 7.40-7.45 (m, 3H), 7.32 (t, 1H,J=7.4 Hz), 7.18 (d, 1H, J=8.0 Hz), 3.67-3.72 (m, 1H), 3.49-3.55 (m, 1H),3.19-3.23 (m, 1H), 2.74-2.84 (m, 2H), 1.71-1.92 (m, 4H). [M+H] calc'dfor C₂₃H₂₂N₂O₂, 359; found 359.

Preparation 74A: 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 39% overall yield from5-methoxy-1-tetralone according to the procedure for Preparation 63A.[M+H] calc'd for C₁₂H₁₇NO, 192; found 192.

Example 74:3-{[(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 22% yield from Preparation 74A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 1.68-1.78 (4H, m), 2.48-2.51(1H, m), 2.61-2.65 (1H, m), 3.07-3.11 (1H, m), 3.42-3.56 (2H, m), 3.76(3H, s), 6.77 (1H, d, J=7.8 Hz), 6.91 (1H, d, J=7.8 Hz), 7.11 (1H, t,J=8.1 Hz), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=5.1 Hz), 8.36 (1H, s).[M+H] Calc'd for C₁₈H₂₀N₂O₃, 313; found, 313.

Preparation 75A: methyl3-{[(6-bromo-3,4-dihydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

To a solution of Preparation 69A (100 mg, 0.42 mmol) in DMA (5 mL) wasadded methyl 3-fluoroisonicotinate (65 mg, 0.42 mmol) at rt. Thereaction was stirred at 170° C. for 1 h in a microwave. The reactionmixture was diluted with water extracted with EtOAc. Organics werewashed with brine, dried (Na₂SO₄), and concentrated. Purification bysilica gel chromatography (5:1 PE/EtOAc) gave 50 mg (32%) of the titlecompound as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ 3.92 (3H, s),4.27-4.28 (2H, m), 4.81-4.82 (2H, m), 5.78-5.80 (1H, m), 7.00-7.08 (3H,m), 7.65-7.69 (2H, m), 7.97 (1H, d, J=5.1 Hz), 8.20 (1H, s).

Preparation 75B: methyl3-{[(6-cyclopropyl-3,4-dihydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 55% yield from Preparation 75Aaccording to the general procedure for Preparation 19C. ¹H NMR (300 MHz,CDCl₃): δ 0.68-0.73 (2H, m), 0.94-1.00 (2H, m), 1.82-1.88 (1H, m), 3.92(3H, s), 4.27-4.30 (2H, m), 4.76-4.79 (2H, m), 5.70-5.72 (1H, m), 6.55(1H, d, J=1.8 Hz), 6.68 (1H, dd, J=1.8, 7.8 Hz), 7.06 (1H, d, J=7.8 Hz),7.64-7.69 (2H, m), 7.96 (1H, d, J=5.1 Hz), 8.23 (1H, s).

Preparation 75C: methyl3-{[(7-cyclopropyl-3,4-dihydro-2H-chromen-4-yl)methyl]amino}pyridine-4-carboxylate

To a solution of Preparation 75B (200 mg, 0.6 mmol) in MeOH (10 mL) andAcOH (2 mL) was added 10% Pd/C (30 mg) under N₂ at rt. The mixture washeated at 80° C. overnight under 2.0 MPa H₂. The reaction was filteredand concentrated in vacuo to give the crude title compound. [M+H] Calc'dfor C₂₀H₂₂N₂O₃, 339; found, 339.

Example 75:3-{[(7-cyclopropyl-3,4-dihydro-2H-chromen-4-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 70% yield from Example 75C accordingto the general hydrolysis procedure outlined for Example 13. ¹H NMR (300MHz, DMSO-d₆): δ 0.58-0.62 (2H, m), 0.87-0.92 (2H, m), 1.79-1.98 (3H,m), 3.05-3.10 (1H, m), 3.44-3.51 (1H, m), 3.63-3.68 (1H, m), 4.11-4.16(2H, m), 6.46 (1H, s), 6.57 (1H, d, J=8.4 Hz), 7.16 (1H, d, J=7.8 Hz),7.57 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=3.6 Hz), 8.41 (1H, s). [M+H]Calc'd for C₁₉H₂₀N₂O₃, 325; found, 325.

Preparation 76A: 5-(cyclopropylmethoxy)-3,4-dihydronaphthalen-1(2H)-one

To a solution of 5-hydroxy-1-tetralone (1.8 g, 11.0 mmol) in butanonewas added (bromomethyl)cyclopropane (1.8 g, 13.2 mmol) and K₂CO₃ (3.0 g,22.0 mmol) at rt. The mixture was heated at 80° C. overnight. Thereaction was cooled to rt, diluted with EtOAc, filtered, andconcentrated. The residue was purified by silica gel chromatography(20:1 PE/EtOAc) to give 1.9 g (78%) of the title compound as a tan oil.¹H NMR (300 MHz, CDCl₃): δ 0.35-0.40 (2H, m), 0.62-0.68 (2H, m),1.27-1.32 (1H, m), 2.05-2.17 (2H, m), 2.64 (2H, t, J=6.6 Hz), 2.96 (2H,t, J=6.0 Hz), 3.86 (2H, d, J=6.9 Hz), 6.98 (1H, d, J=8.1 Hz), 7.24 (1H,t, J=8.7 Hz), 7.65 (1H, d, J=8.1 Hz).

Preparation 76B:1-[5-(cyclopropylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 33% overall yield from Preparation76A according to the procedure for Preparation 63A, with the exceptionthat the dehydration step ran for 2 hr instead of overnight. [M+H]calc'd for C₁₅H₂₁NO, 232; found 232.

Example 76:3-({[(5-(cyclopropylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid

The title compound was prepared in 6% yield from Preparation 76B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 0.30-0.35 (2H, m), 0.53-0.59(2H, m), 1.19-1.24 (1H, m), 1.67-1.83 (4H, m), 2.53-2.57 (1H, m),2.64-2.73 (1H, m), 3.07-3.09 (1H, m), 3.34-3.59 (2H, m), 3.75-3.85 (2H,m), 6.72 (1H, d, J=7.8 Hz), 6.88 (1H, d, J=4.8 Hz), 7.03-7.09 (1H, m),7.55 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.2 Hz), 8.36 (1H, s). [M+H]Calc'd for C₂₁H₂₄N₂O₃, 352; Found, 352.

Preparation 77A: 5-phenoxy-3,4-dihydronaphthalen-1(2H)-one

To a solution of 5-hydroxy-1-tetralone (4.5 g, 28.0 mmol) andiodobenzene (24.0 g, 168.0 mmol) in DMF (50 mL) was added NaH (1.2 g,30.0 mmol) at rt. The mixture was heated to 50° C. until the solid wasdissolved and then cooled. To the mixture was added CuCl (2.8 g, 28.0mmol); followed by tris(dioxa 3,6-heptyl)amine (2.7 g, 8.4 mmol). Themixture was heated at 145° C. overnight. The reaction was diluted withwater, extracted with EtOAc, washed with brine, dried (Na₂SO₄), andconcentrated. Purification by silica gel chromatography (20:1 PE/EtOAc)gave 1.2 g (18%) of the title compound as a yellow oil. [M+H] calc'd forC₁₆H₁₄O₂, 239; found 239.

Preparation 77B: 5-phenoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 81% overall yield from Preparation77A according to the procedure for Preparation 63A. [M+H] calc'd forC₁₇H₁₉NO, 254; found 254.

Example 77:3-{[(5-phenoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 3% yield from Preparation 77B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, CF₃CO₂D): δ 1.71-1.95 (4H, m), 2.59-2.67(2H, m), 3.22-3.26 (1H, m), 3.56-3.61 (2H, m), 6.74-6.83 (3H, m),6.92-7.04 (3H, m), 7.14-7.19 (2H, m), 7.76-7.78 (1H, m), 8.05 (1H, s),8.29 (1H, d, J=5.7 Hz). [M+H] Calc'd for C₂₃H₂₂N₂O₃, 374; found, 374.

Preparation 78A: 1-(3,4-dihydro-2H-thiochromen-4-yl)methanamine

The title compound was prepared in 34% overall yield fromthiochroman-4-one according to the procedure for Preparation 63A, withthe exception that the dehydration step ran for 2 hr instead ofovernight. [M+H] calc'd for C₁₀H₁₃NS, 180; found 180.

Example 78:3-[(3,4-dihydro-2H-thiochromen-4-ylmethyl)amino]pyridine-4-carboxylicacid

The title compound was prepared in 24% yield from Preparation 78A and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 1.87-1.95 (1H, m), 2.21-2.28(1H, m), 2.92-2.99 (1H, m), 3.18-3.27 (2H, m), 3.48-3.53 (2H, m),6.97-7.02 (1H, m), 7.07-7.09 (2H, m), 7.21 (1H, d, J=7.8 Hz), 7.57 (1H,d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd forC₁₆H₁₆N₂O₂S, 301; found, 301.

Preparation 79A: 6-(3,3,3-trifluoropropoxy)-3,4-dihydronaphthalen-1(2H)-one

6-Hydroxy-1-tetralone (3.5 g, 21.6 mmol), 3,3,3-trifluoro-1-propanol(4.93 g, 43.2 mmol) and triphenylphosphine (11.3 g, 43.2 mmol) werecombined in THF (80 mL). DIAD (8.7 g, 43.2 mmol) was added, and thereaction stirred overnight at rt. The solution was diluted with EtOAc(100 mL) and washed with brine. Organics were dried (MgSO₄) andconcentrated. Purification by silica gel chromatography (10-50%EtOAc/hexanes) gave 2.93 g (53%) of the title compound as a clear oil.¹H NMR (400 MHz, DMSO-d₆): δ 8.02 (d, 1H, J=8.7 Hz), 6.82 (dd, 1H,J=8.7, 2.5 Hz), 6.71 (d, 1H, J=2.4 Hz), 4.25 (t, 2H, J=6.6 Hz), 2.93 (t,2H, J=6.1 Hz), 2.59-2.71 (m, 4H), 2.08-2.16 (m, 2H). [M+H] calc'd forC₁₃H₁₃F₃O₂, 259; found 259.

Preparation 79B:1-[6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1yl]methanamine, hydrochloride

The title compound was prepared in 47% yield from Preparation 79Aaccording to the general procedure for Preparation 60A. ¹H NMR (400 MHz,DMSO-d₆): δ 8.07 (br s, 3H), 7.17 (d, 1H, J=8.6 Hz), 6.76 (dd, 1H,J=8.5, 2.7 Hz), 6.69 (d, 1H, J=2.6 Hz), 4.16 (t, 2H, J=5.9 Hz),3.00-3.06 (m, 2H), 2.5-2.0 (m, 5H), 1.61-1.86 (m, 4H). [M+H] calc'd forC₁₄H₁₈F₃NO, 274; found 274.

Example 79:3-({[(6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid

The title compound was prepared in 16% yield from Preparation 79B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 5. ¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (s, 1H), 7.80 (d, 1H,J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.23 (d, 1H, J=8.5 Hz), 6.68-6.75 (m,2H), 4.16 (t, 2H, J=5.9 Hz), 3.49-3.55 (m, 1H), 3.34-3.41 (m, 1H),3.02-3.06 (m, 1H), 2.67-2.81 (m, 4H), 1.64-1.83 (m, 4H). [M+H] calc'dfor C₂₀H₂₁F₃N₂O₃, 395; found 395.

Preparation 80A: 6-phenoxy-3,4-dihydronaphthalen-1(2H)-one

The title compound was prepared in 21% yield from 6-hydroxy-1-tetraloneaccording to the procedure for Preparation 77A. ¹H NMR (300 MHz, CDCl₃):δ 2.09-2.18 (2H, m), 2.64 (2H, t, J=6.01 Hz), 2.91 (2H, t, J=6.01 Hz),6.78 (1H, d, J=2.1 Hz), 6.88 (1H, dd, J=2.7, 8.7 Hz), 7.10 (2H, d, J=7.5Hz), 7.22 (1H, t, J=7.5 Hz), 7.45 (2H, t, J=7.8 Hz), 8.05 (1H, d, J=8.7Hz).

Preparation 80B: 6-phenoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 70% overall yield from Preparation80A according to the procedure for Preparation 63A. [M+H] calc'd forC₁₇H₁₉NO, 254; found 254.

Example 80:3-{[(5-phenoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 27% yield from Preparation 80B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ ¹H NMR (300 MHz, DMSO-d₆): δ1.62-1.86 (4H, m), 2.67-2.71 (2H, m), 3.09-3.13 (1H, m), 3.43-3.47 (1H,m), 3.50-3.58 (1H, m), 6.74-6.79 (2H, m), 6.97 (2H, d, J=7.5 Hz), 7.11(1H, t, J=7.5 Hz), 7.32-7.40 (3H, m), 7.58 (1H, d, J=5.1 Hz), 7.84 (1H,d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₃H₂₂N₂O₃, 375; found,375.

Preparation 81A: 6-(cyclopropylmethoxy)-3,4-dihydronaphthalen-1(2H)-one

To a solution of 6-hydroxy-1-tetralone (2.0 g, 12.3 mmol) in ACN (30 mL)was added (bromomethyl)cyclopropane (2.0 g, 14.7 mmol) and K₂CO₃ (3.4 g,24.6 mmol) at rt. The mixture was heated at 80° C. overnight. After thereaction was cooled to rt, it was diluted with EtOAc, filtered, andconcentrated. The residue was purified by column chromatography (20:1PE/EtOAc) to give 2.3 g (87%) of the title compound as a yellow solid.¹H NMR (300 MHz, CDCl₃): δ 0.35-0.40 (2H, m), 0.65-0.71 (2H, m),1.25-1.32 (1H, m), 2.08-2.16 (2H, m), 2.62 (2H, t, J=6.3 Hz), 2.93 (2H,t, J=6.0 Hz), 3.87 (2H, d, J=7.2 Hz), 6.71 (1H, s), 6.83 (1H, dd, J=2.1,8.4 Hz), 8.01 (1H, d, J=8.4 Hz).

Preparation 81B:1-[6-(cyclopropylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 33% overall yield from Preparation81A according to the procedure for Preparation 63A, with the exceptionthat the dehydration step ran for 2 h instead of overnight. [M+H] calc'dfor C₁₅H₂₁NO, 232; found 232.

Example 81:3-({[(6-(cyclopropylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid

The title compound was prepared in 22% yield from Preparation 81B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 0.29-0.34 (2H, m), 0.52-0.58(2H, m), 1.16-1.20 (1H, m), 1.63-1.83 (4H, m), 2.66-2.70 (2H, m),3.02-3.05 (1H, m), 3.40-3.45 (1H, m), 3.51-3.52 (1H, m), 3.75 (2H, d,J=6.9 Hz), 6.63 (1H, d, J=2.1 Hz), 6.68 (1H, dd, J=2.7, 8.4 Hz), 7.19(1H, d, J=8.7 Hz), 7.55 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.35(1H, s). [M+H] Calc'd for C₂₁H₂₄N₂O₃, 353; found, 353.

Example 82:3{[(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 18% yield from1-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)methanamine and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 53. ¹H NMR (400 MHz, DMSO-d₆): δ 13.36 (br s, 1H), 8.35 (s,1H), 7.83 (d, 1H, J=5.0 Hz), 7.72 (br s, 1H), 7.56 (d, 1H, J=5.0 Hz),7.01-7.08 (m, 2H), 6.52-6.62 (m, 2H), 3.45-3.51 (m, 2H), 3.04-3.32 (m,3H), 2.85 (s, 3H), 1.89-1.95 (m, 2H). [M+H] calc'd for C₁₇H₁₉N₃O₂, 298;found 298.

Preparation 83A: methyl3-{[(7-phenyl-3,4-dihydro-2H-chromen-4-yl)methyl]amino}pyridine-4-carboxylate

To a solution of Preparation 69D (700 mg, 2.9 mmol) in DMA (10 mL) wasadded methyl 3-fluoropyridine-4-carboxylate (500 mg, 3.2 mmol) at rt.The reaction was stirred at 170° C. for 1 hr in a microwave.Purification by silica gel chromatography (PE:EtOAc=2:1) gave 380 mg(35%) of the title compound as a yellow oil. [M+H] calc'd forC₂₃H₂₂N₂O₃, 375; found 375.

Preparation 83B and Preparation 84B: methyl3-({[(4S)-7-phenyl-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate;methyl3-({[(4R)-7-phenyl-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 83A (380 mg) was separated by chiral HPLC (Column: ChiralcelOD-H, 250 mm*4.6 mm 5 μm; Mobile phase: Hex:IPA=40:60; F: 1.0 mL/min; W:230 nm; T=30° C.) to give to give the two enantiomers: 120 mg (32%) ofthe first isomer eluted at 10.39 min and 100 mg (26%) of the secondisomer eluted at 13.88 min.

Example 83 and Example 84:3-({[(4S)-7-phenyl-3,4-dihydro-2H-chromen-4-yl]methyl}-amino)pyridine-4-carboxylicacid;3-({[(4R)-7-phenyl-3,4-dihydro-2H-chromen-4-yl]methyl}-amino)pyridine-4-carboxylicacid

The title compounds were prepared in 83% to 85% yield from Preparation83B and Preparation 84B according to the general hydrolysis procedureoutlined for Example 61 and Example 62. NMR and MS for each of the titlecompounds matched Example 69.

Preparation 85A: 7-(3-fluorophenyl)-3,4-dihydro-2H-chromen-4-one

To a solution of 6-bromo-3,4-dihydro-2H-chromen-4-one (1.5 g, 6.6 mmol),3-fluorophenylboronic acid (1.39 g, 9.9 mmol) and sodium carbonate (2.1g, 19.8 mmol) in dioxane (20 mL) and water (1 mL) was addedPd(PPh₃)₄(382 mg, 0.3 mmol) at rt. The solution was heated at 100° C.overnight. The reaction was filtered, concentrated, and purified bysilica gel chromatography (PE:EtOAc:DCM=10:1:2) to give 1.4 g (88%) ofthe title compound as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 2.86(2H, t, J=6.6 Hz), 4.60 (2H, t, J=6.6 Hz), 7.11-7.14 (1H, m), 7.18 (1H,d, J=1.5 Hz), 7.23-7.29 (2H, m), 7.32-7.45 (2H, m), 7.98 (1H, d, J=8.1Hz).

Preparation 85B:[7-(3-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methanamine

The title compound was prepared in 27% yield from Preparation 85Aaccording to the general procedure for Preparation 63A. [M+H] calc'd forC₁₆H₁₆FNO, 258; found 258.

Preparation 85C: methyl3-({[7-(3-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared from in 31% yield from Preparation 85Baccording to the general procedure outlined for Preparation 83A. [M+H]calc'd for C₂₃H₂₁FN₂O₃, 393; found 393.

Preparation 85D and Preparation 86D: methyl3-({[(4S)-7-(3-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate;methyl3-({[(4R)-7-(3-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 85C (88 mg) was separated by chiral HPLC (Column: ChiralcelOD-H, 250 mm*4.6 mm 5 um; Mobile phase: Hex:IPA=70:30; F: 1.0 mL/min; W:230 nm; T=30° C.) to give to give the two enantiomers: 27 mg (31%) ofthe first isomer eluted at 9.11 min and 25 mg (28%) of the second isomereluted at 10.30 min.

Example 85 and Example 86:3-({[(4S)-7-(3-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylicacid;3-({[(4R)-7-(3-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylicacid

The title compounds were prepared in 78% to 83% yield from Preparation85D and Preparation 86D according to the general hydrolysis procedureoutline for Example 61 and Example 62. NMR and MS for each of the titlecompounds were identical: ¹H NMR (300 MHz, DMSO-d₆): δ 1.92-2.03 (2H,m), 3.17-3.21 (1H, m), 3.56-3.59 (1H, m), 3.71-3.73 (1H, m), 4.21-4.26(2H, m), 7.11 (1H, s), 7.16-7.21 (2H, m), 7.40-7.49 (4H, m), 7.58 (1H,d, J=4.8 Hz), 7.86 (1H, d, J=5.1 Hz), 8.46 (1H, s). [M+H] Calc'd forC₂₂H₁₉FN₂O₃, 379; Found, 379.

Preparation 87A and Preparation 88A: methyl3-({[(4S)-7-cyclopropyl-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate;methyl3-({[(4R)-7-cyclopropyl-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 75C (80 mg) was separated by chiral HPLC (Column: Chiralcel1A, Mobile phase: CO₂:MeOH=60:40 (0.2% DEA) to give to give the twoenantiomers: 20 mg (25%) of the first isomer eluted at 2.37 min and 22mg (28%) of the second isomer eluted at 4.26 min.

Example 87 and Example 88:3-({[(4S)-7-cyclopropyl-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylicacid;3-({[(4R)-7-cyclopropyl-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylicacid

The title compounds were prepared in 48% to 68% yield from Preparation87A and Preparation 88A according to the general hydrolysis procedureoutlined for Example 61 and Example 62. NMR and MS for each of the titlecompounds matched Example 75.

Preparation 89A: 6-(2-phenylethoxy)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (2.0 g, 12.3mmol) and (2-bromoethyl)benzene (4.8 g, 25.8 mmol) in ACN (20 mL) wasadded potassium carbonate (3.4 g, 24.6 mmol) at rt. The solution washeated at reflux overnight. The reaction was filtered, concentrated, andpurified by silica gel chromatography (PE:EtOAc:DCM=10:1:2) to give 2.0g (61%) of the title compound as a brown oil. ¹H NMR (300 MHz, CDCl₃): δ2.08-2.16 (2H, m), 2.62 (2H, t, J=6.3 Hz), 2.92 (2H, t, J=6.3 Hz), 3.13(2H, t, J=7.2 Hz), 2.92 (2H, t, J=7.2 Hz), 6.71 (1H, d, J=2.1 Hz), 6.83(1H, dd, J=2.4, 8.7 Hz), 7.27-7.38 (5H, m), 8.01 (1H, dd, J=8.7 Hz).

Preparation 89B:[6-(2-phenylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 30% yield from Preparation 89Aaccording to the general procedure for Preparation 63A, with theexception that the dehydration step reaction time was 10 min. [M+H]calc'd for C₁₉H₂₃NO, 282; found 282.

Example 89:3-({[6-(2-phenylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid

The title compound was prepared in 9% yield from Preparation 89B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 1.63-1.83 (4H, m), 2.66-2.71(2H, m), 2.98-3.03 (3H, m), 3.40-3.44 (1H, m), 3.50-3.52 (1H, m), 4.13(2H, t, J=6.6 Hz), 6.66-6.72 (2H, m), 7.19-7.21 (2H, m), 7.23-7.32 (4H,m), 7.54 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.35 (1H, s). [M+H]Calc'd for C₂₅H₂₆N₂O₃, 403; Found, 403.

Preparation 90A:6-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (200 mg, 1.2mmol) and 2,2,2-trifluoroethyl tosylate (345 mg, 1.4 mmol) in DMF (10mL) was added potassium carbonate (339 mg, 2.5 mmol) at rt. The solutionwas heated at 100° C. overnight. The reaction was cooled, diluted withwater (20 mL), and extracted with EtOAc (20 mL×3). Organics were dried(Na₂SO₄) and concentrated to give 250 mg (83%) of the title compound asa yellow solid. ¹H NMR (300 MHz, CDCl₃): δ 2.12-2.16 (2H, m), 2.64 (2H,t, J=6.3 Hz), 2.95 (2H, t, J=6.3 Hz), 4.34-4.46 (2H, m), 6.78 (1H, d,J=2.4 Hz), 6.87 (1H, dd, J=2.4, 8.7 Hz), 8.05 (1H, dd, J=8.7 Hz).

Preparation 90B:[6-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 13% yield from Preparation 90Aaccording to the general procedure for Preparation 63A, with theexception that the dehydration step reaction time was 10 min. [M+H]calc'd for C₁₃H₁₆F₃NO, 260; found 260.

Example 90:3-({[6-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid

The title compound was prepared in 29% yield from Preparation 90B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 1.64-1.84 (4H, m), 2.68-2.72(2H, m), 3.05-3.07 (1H, m), 3.41-3.46 (1H, m), 3.53-3.54 (1H, m),4.65-4.74 (2H, m), 6.80-6.84 (2H, m), 7.27 (1H, d, J=8.1 Hz), 7.55 (1H,d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd forC₁₉H₁₉F₃N₂O₃, 381; Found, 381.

Preparation 91A:7-(2-cyclopropylethynyl)-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of 7-bromochroman-4-one (2.0 g, 8.8 mmol) in DMF (10 mL)was added CuI (380 mg, 1.7 mmol), Pd(PPh₃)Cl₂ (540 mg, 0.8 mmol) andtriethylamine (5 mL) under nitrogen at rt. The suspension was warmed to100° C. and then cyclopropylacetylene (1.1 g, 17.6 mmol) was addeddropwise. The mixture was stirred at 100° C. under nitrogen for 2 hr.The reaction mixture was cooled to rt, poured into water, and extractedwith EtOAc. Organics were separated and washed with brine, dried(Na₂SO₄), and concentrated. The residue was purified by silica gelchromatography to give 1.65 g (88%) of the title compound as a tansolid. ¹H NMR (300 MHz, CDCl₃): δ 0.83-0.93 (4H, m), 1.44-1.49 (1H, m),2.79 (2H, t, J=6.6 Hz), 4.52 (2H, t, J=6.6 Hz), 6.96-7.00 (2H, m), 7.79(1H, d, J=7.8 Hz). [M+H] calc'd for C₁₄H₁₂O, 213; found 213.

Preparation 91B:7-(2-cyclopropylethyl)-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of Preparation 91A (520 mg, 2.4 mmol) in MeOH (15 mL) wasadded 10% Pd/C (190 mg) at rt under nitrogen. The suspension was stirredovernight at rt under 50 psi of hydrogen. The reaction mixture wasfiltered and concentrated. The residue was purified by silica gelchromatography to give 460 mg (86%) of the title compound as a colorlessoil. [M+H] calc'd for C₁₄H₁₆O, 217; found 217.

Preparation 91C:[7-(2-cyclopropylethyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 14% yield from Preparation 91Baccording to the general procedure for Preparation 63A, with theexception that the dehydration step reaction time was 1 hr. [M+H] calc'dfor C₁₅H₂₁NO, 232; found 232.

Example 91D: methyl3-({[7-(2-cyclopropylethyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared from in 21% yield from Preparation 91Caccording to the general procedure outlined for Preparation 83A. [M+H]calc'd for C₂₂H₂₆N₂O₃, 367; found 367.

Example 91:3-({[7-(2-cyclopropylethyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid

The title compound was prepared in 63% yield from Preparation 91Daccording to the general hydrolysis procedure outlined for Examples 61and 62. ¹H NMR (300 MHz, CD₃OD): δ 0.01-0.05 (2H, m), 0.38-0.44 (2H, m),0.65-0.70 (1H, m), 1.41-1.49 (2H, m), 1.96-2.03 (1H, m), 2.11-2.17 (1H,m), 2.61 (2H, t, J=7.5 Hz), 3.19-3.23 (1H, m), 3.53-3.60 (1H, m),3.69-3.75 (1H, m), 4.16-4.27 (2H, m), 6.63 (1H, s), 6.69 (1H, d, J=7.5Hz), 7.14 (1H, d, J=8.1 Hz), 7.92 (1H, d, J=5.4 Hz), 8.21 (1H, d, J=5.4Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₁H₂₄N₂O₃, 352; Found, 352.

Preparation 92A: ethyl 4-[3-(trifluoromethoxy)phenyl]butanoate

4-Ethoxy-4-oxobutylzinc bromide solution (25 mL, 0.5 M in THF, 12.5mmol) was added to a solution of 1-bromo-3-(trifluoromethoxy)benzene(2.6 g, 10.8 mmol) in THF (10 mL) under N₂. Pd(dppf)Cl₂ (1.18 g, 1.62mmol) was added, and the reaction was heated at reflux for 3 hr. Thesolution was concentrated and purified by silica gel chromatography(0-20% EtOAc/hexanes) to give 1.22 g (41%) of the title compound as aclear oil. ¹H NMR (400 MHz, DMSO-d₆): δ 1.26 (3H, t, J=7.2 Hz),1.91-2.00 (2H, m), 2.32 (2H, t, J=7.4 Hz), 2.67 (2H, t, J=7.4 Hz), 4.13(2H, q, J=7.2 Hz), 7.03-7.07 (2H, m), 7.11 (1H, d, J=7.7 Hz), 7.30 (1H,t, J=7.7 Hz).

Preparation 92B: 4-[3-(trifluoromethoxy)phenyl]butanoic acid

Preparation 92A (1.22 g, 4.42 mmol) was stirred in MeOH (10 mL) with 5NNaOH (2 mL) at rt overnight. The solution was neutralized with HOAc andconcentrated. Purification by silica gel chromatography (5-10% MeOH/DCM)gave 1.02 g (92%) of the title compound as a clear oil. ¹H NMR (400 MHz,DMSO-d₆): δ 1.93-2.01 (2H, m), 2.39 (2H, t, J=7.4 Hz), 2.70 (t, 2H,J=7.4 Hz), 7.04-7.13 (3H, m), 7.30 (1H, t, J=7.7 Hz), 11.33 (1H, br s).

Preparation 92C: 6-(trifluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-one

Preparation 93B (1.02 g, 4.11 mmol) was heated in PPA (5 mL) at 82° C.for 2 hr. The reaction was cooled, slowly quenched with sat NaHCO₃, andextracted with EtOAc (3×). Organics were dried (MgSO₄) and concentrated.Purification by silica gel chromatography (20-60% EtOAc/hexanes) gave630 mg (67%) of the title compound as a clear oil. ¹H NMR (400 MHz,DMSO-d₆): δ 2.13-2.20 (2H, m), 2.67 (2H, t, J=6.4 Hz), 2.99 (2H, t,J=6.1 Hz), 7.09 (1H, s), 7.13 (1H, d, J=8.7 Hz), 8.08 (1H, d, J=8.6 Hz).[M+H] calc'd for C₁₁H₉F₃O₂, 231; found 231.

Preparation 92D:[6-(trifluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 34% overall yield from Preparation92C according to the procedure for Preparation 63A, with the exceptionthat the dehydration step ran for 2 hr instead of overnight. ¹H NMR (400MHz, Me₃OD): δ 1.78-2.00 (4H, m), 2.76-2.90 (2H, m), 3.07-3.15 (1H, m),3.20-3.33 (2H, m), 7.02 (1H, s), 7.07 (1H, d, J=8.6 Hz), 7.37 (1H, d,J=8.5 Hz). [M+H] calc'd for C₁₂H₁₄F₃NO, 246; found 246.

Example 92:3-({[6-(trifluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid

The title compound was prepared in 14% yield from Preparation 92D and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 1.66-1.88 (4H, m), 2.73-2.84(2H, m), 3.12-3.16 (1H, m), 3.44-3.62 (2H, m), 7.09-7.12 (2H, m), 7.44(1H, d, J=9.1 Hz), 7.57 (1H, d, J=5.0 Hz), 7.71 (1H, br s), 7.84 (1H, d,J=5.0 Hz), 8.37 (1H, s). [M+H] calc'd for C₁₈H₁₇F₃N₂O₃, 367; found 367.

Preparation 93A: 7-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4-one

The title compound was prepared in 99% yield using 4-fluorophenylboronicacid in the general procedure for Preparation 85A. ¹H NMR (300 MHz,CDCl₃): δ 2.86 (2H, t, J=6.3 Hz), 4.95 (2H, t, J=6.3 Hz), 7.13-7.24 (4H,m), 7.58 (2H, dd, J=5.7, 8.4 Hz), 7.96 (1H, d, J=8.1 Hz).

Preparation 93B:[7-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methanamine

The title compound was prepared in 17% yield from Preparation 93Aaccording to the general procedure for Preparation 63A. [M+H] calc'd forC₁₆H₁₆FNO, 258; found 258.

Preparation 93C: methyl3-({[7-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared from in 35% yield from Preparation 93Baccording to the general procedure outlined for Preparation 83A. [M+H]calc'd for C₂₃H₂₁FN₂O₃, 393; found 393.

Preparation 93D and Preparation 94D: methyl3-({[(4S)-7-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate;methyl3-({[(4R)-7-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 93C (200 mg) was separated by chiral HPLC (Column: ChiralcelID; Mobile phase: CO₂:MeOH=60:40 with −0.2% DEA) to give to give the twoenantiomers: 50 mg (25%) of the first isomer eluted at 3.92 min and 60mg (30%) of the second isomer eluted at 5.55 min.

Example 93 and Example 94:3-({[(4S)-7-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylicacid;3-({[(4R)-7-(4-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylicacid

The title compounds were prepared in 70% to 92% yield from Preparation93D and Preparation 94D according to the general hydrolysis procedureoutline for Example 61 and Example 62. NMR and MS for each of the titlecompounds were identical: ¹H NMR (300 MHz, DMSO-d₆): δ 1.87-2.04 (2H,m), 3.14-3.20 (1H, m), 3.50-3.59 (1H, m), 3.70-3.77 (1H, m), 4.16-4.25(2H, m), 7.04 (1H, d, J=1.8 Hz), 7.14 (1H, dd, J=1.5, 7.8 Hz), 7.26 (2H,t, J=9.0 Hz), 7.39 (1H, d, J=8.1 Hz), 7.58 (1H, d, J=4.8 Hz), 7.64-7.68(2H, m), 7.85 (1H, d, J=5.1 Hz), 8.45 (1H, s). [M+H] Calc'd forC₂₂H₁₉FN₂O₃, 379; Found, 379.

Preparation 95A: 7-(2-fluorophenyl)-3,4-dihydro-2H-chromen-4-one

The title compound was prepared in 36% yield using 2-fluorophenylboronicacid in the general procedure for Preparation 85A.

Preparation 95B:[7-(2-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methanamine

The title compound was prepared in 33% yield from Preparation 95Aaccording to the general procedure for Preparation 63A. [M+H] calc'd forC₁₆H₁₆FNO, 258; found 258.

Preparation 95C: methyl3-({[7-(2-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared from in 36% yield from Preparation 95Baccording to the general procedure outlined for Preparation 83A. [M+H]calc'd for C₂₃H₂₁FN₂O₃, 393; found 393.

Preparation 95D and Preparation 96D: methyl3-({[(4S)-7-(2-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate;methyl3-({[(4R)-7-(2-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 95C (200 mg) was separated by chiral HPLC (Column: ChiralcelID, 250 mm*4.6 mm 5 μm; Mobile phase: Hex:IPA=80:20; F: 1.0 mL/min; W:230 nm; T=30° C.) to give to give the two enantiomers: 70 mg (35%) ofthe first isomer eluted at 4.52 min and 69 mg (34%) of the second isomereluted at 5.68 min.

Example 95 and Example 96:3-({[(4S)-7-(2-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylicacid;3-({[(4R)-7-(2-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylicacid

The title compounds were prepared in 77% to 91% yield from Preparation95D and Preparation 96D according to the general hydrolysis procedureoutline for Example 61 and Example 62. NMR and MS for each of the titlecompounds were identical: ¹H NMR (300 MHz, DMSO-d₆): δ 1.91-2.04 (2H,m), 3.18-3.23 (1H, m), 3.53-3.61 (1H, m), 3.73-3.79 (1H, m), 4.17-4.26(2H, m), 6.94 (1H, s), 7.04 (1H, d, J=8.1 Hz), 7.25-7.32 (2H, m),7.36-7.52 (3H, m), 7.72 (1H, d, J=5.1 Hz), 7.90 (1H, d, J=4.5 Hz), 8.49(1H, s). [M+H] Calc'd for C₂₂H₁₉FN₂O₃, 379; Found, 379.

Preparation 97A:6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (1.0 g, 6.0mmol), 2-cyclopropylethanol (640 mg, 7.0 mmol) and triphenylphosphine(3.25 g, 12 mmol) in THF (100 mL) was added DEAD (2.13 g, 12 mmol) at 0°C. The reaction was stirred at rt overnight. The solution wasconcentrated and purified by silica gel chromatography (PE:EtOAc=12:1)to give 470 mg (33%) of the title compound as a red oil. ¹H NMR (300MHz, CDCl₃): δ 0.13-0.15 (2H, m), 0.50-0.52 (2H, m), 0.86-0.93 (1H, m),1.68-1.74 (2H, m), 2.11-2.15 (2H, m), 2.64 (2H, t, J=6.3 Hz), 2.93 (2H,t, J=6.0 Hz), 4.10 (2H, t, J=6.6 Hz), 6.73 (1H, s), 6.83 (1H, dd, J=2.4,8.7 Hz), 8.02 (1H, d, J=8.7 Hz).

Preparation 97B:[6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 73% yield from Preparation 97Aaccording to the general procedure for Preparation 63A, with theexception that the dehydration step reaction time was 10 min. [M+H]calc'd for C₁₆H₂₃NO, 246; found 246.

Preparation 97C: methyl3-({[6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 18% yield from Preparation 97B andmethyl 3-fluoroisonicotinate according to the procedure for thepreparation of Example 83A. [M+H] Calc'd for C₂₃H₂₈N₂O₃, 381; Found,381.

Preparation 97D and Preparation 98D: methyl3-({[(1S)-6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;methyl3-({[(1R)-6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 97C (100 mg) was separated by chiral HPLC (Column: ChiralcelID, 250 mm*4.6 mm 5 μm; Mobile phase: CO₂:MeOH (0.2% DEA)=70:30; F: 1.0mL/min; W: 230 nm; T=30° C.) to give to give the two enantiomers: 15 mg(15%) of the first isomer eluted at 3.82 min and 20 mg (20%) of thesecond isomer eluted at 4.94 min.

Example 97 and Example 98: 3-({[(1S)-6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicacid;3-({[(1R)-6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicacid

The title compounds were prepared in 71% to 74% yield from Preparation97D and Preparation 98D according to the general hydrolysis procedureoutline for Example 61 and Example 62. NMR and MS for each of the titlecompounds were identical: ¹H NMR (300 MHz, DMSO-d₆): δ 0.09-0.12 (2H,m), 0.40-0.44 (2H, m), 0.77-0.86 (1H, m), 1.58-1.65 (3H, m), 1.75-1.84(3H, m), 2.66-2.71 (2H, m), 3.00-3.05 (1H, m), 3.38-3.44 (1H, m),3.50-3.56 (1H, m), 3.96 (2H, t, J=6.6 Hz), 6.65-6.72 (2H, m), 7.20 (1H,d, J=8.1 Hz), 7.55 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=4.8 Hz), 8.35 (1H,s). [M+H] Calc'd for C₂₂H₂₆N₂O₃, 367; Found, 367.

Preparation 99A: methyl3-({[(6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared from in 45% yield from Preparation 79Baccording to the general procedure outlined for Preparation 83A. [M+H]Calc'd for C₂₁H₂₃F₃N₂O₃, 407; Found, 407.

Preparation 99B and Preparation 100B: methyl3-({[(1S)-6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;methyl3-({[(1R)-6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 99A (380 mg) was separated by chiral HPLC (Column: ChiralcelIF, 250 mm*4.6 mm 5 μm; Mobile phase: CO₂:MeOH (0.2% DEA)=60:40; F: 1.0mL/min; W: 230 nm; T=30° C.) to give to give the two enantiomers: 80 mg(21%) of the first isomer eluted at 2.83 min and 70 mg (18%) of thesecond isomer eluted at 3.84 min.

Example 99 and Example 100:3-({[(1S)-6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicacid;3-({[(1R)-6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicacid

The title compounds were prepared in 74% to 78% yield from Preparation99B and Preparation 100B according to the general hydrolysis procedureoutline for Example 61 and Example 62. NMR and MS for each of the titlecompounds were identical: ¹H NMR (300 MHz, DMSO-d₆): δ 1.63-1.84 (4H,m), 2.67-2.82 (4H, m), 3.02-3.06 (1H, m), 3.41-3.45 (1H, m), 3.51-3.58(1H, m), 4.15 (2H, t, J=6.0 Hz), 6.69-6.75 (2H, m), 7.21 (1H, d, J=8.4Hz), 7.57 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.36 (1H, s). [M+H]Calc'd for C₂₀H₂₁F₃N₂O₃, 395; Found, 395.

Example 101:3-({[6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridazine-4-carboxylicacid

To a solution of Preparation 79B (150 mg, 0.55 mmol) in DMA (5 mL) wasadded 3-chloropyridazine-4-carbonitrile (84 mg, 0.6 mmol) at rt. Thereaction was stirred for 1 hr at 170° C. in a microwave. The solutionwas diluted with H₂O (10 mL) and extracted with EtOAc (20 mL×3).Organics were washed with brine (30 mL), dried (Na₂SO₄), andconcentrated to give crude3-({[6-(3,3,3-trifluoropropoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridazine-4-carbonitrileas a brown oil. This crude intermediate was stirred in EtOH (5 mL) andH₂O (5 mL). NaOH (110 mg, 2.8 mmol) was added, and the reaction wasstirred at 90° C. for 3 hr. The solution was concentrated and purifiedby prep-HPLC to give 50 mg (23%) of the title compound as a brown solid.¹H NMR (300 MHz, CD₃OD): δ 1.77-1.99 (4H, m), 2.62-2.83 (4H, m),3.19-3.23 (1H, m), 3.64-3.67 (1H, m), 3.77-3.79 (1H, m), 4.18 (2H, t,J=6.0 Hz), 6.69-6.75 (2H, m), 7.23 (1H, d, J=8.1 Hz), 8.05 (1H, d, J=4.5Hz), 8.48 (1H, d, J=4.2 Hz). [M+H] Calc'd for C₁₉H₂₀F₃N₃O₃, 396; Found,396.

Preparation 102A: 5-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 6-methoxy-1-tetralone (200 mg, 1.1 mmol) in ACN (20 mL)was added Selectfluor (603 mg, 1.7 mmol) at rt, and the reaction wasstirred at 40° C. overnight. The reaction was filtered and concentrated.The residue was dissolved in EtOAc (40 mL), filtered, and concentrated.Purification by silica gel chromatography (PE:EtOAc:DCM=20:1:2) gave 90mg (41%) of the title compound as a yellow solid. [M+H] Calc'd forC₁₁H₁₁FO₂, 195; Found, 195.

Preparation 102B:(5-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 16% yield from Preparation 90Aaccording to the general procedure for Preparation 63A, with theexception that the dehydration step reaction time was 10 min. [M+H]calc'd for C₁₂H₁₆FNO, 210; found 210.

Example 102:3-{[(5-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 25% yield from Preparation 102B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (300 MHz, DMSO-d₆): δ 1.68-1.82 (4H, m), 2.62-2.70(2H, m), 3.06-3.10 (1H, m), 3.41-3.48 (1H, m), 3.53-3.58 (1H, m), 3.79(3H, s), 6.95 (1H, t, J=8.4 Hz), 7.10 (1H, d, J=8.7 Hz), 7.55 (1H, d,J=5.1 Hz), 7.83 (1H, d, J=4.8 Hz), 8.36 (1H, s). [M+H] Calc'd forC₁₈H₁₉FN₂O₃, 331; Found, 331.

Preparation 103A: (3E)-4-(2,3-dimethylphenyl)but-3-enoic acid

To a solution of 2,3-dimethylbenzaldehyde (17.0 g, 41.0 mmol) in THF (40mL) was added NaHMDS (41.1 mL, 82.1 mmol) at −20° C., and the reactionwas stirred for 20 min. (2-Carboxyethyl)triphenylphosphonium bromide(5.0 g, 37.3 mmol) was added to the reaction at −78° C., and reactionwas stirred while warming to rt overnight. The solution was diluted withwater (50 mL) and extracted with EtOAc (50×3 mL). Organics were washedwith brine (50 mL), dried (Na₂SO₄), and concentrated to give 7.00 g(99%) of the crude title compound as a yellow solid. [M+H] calc'd forC₁₂H₁₄O₂, 191; found 191.

Preparation 103B: 4-(2,3-dimethylphenyl)butanoic acid

To a solution of Preparation 103A (7.0 g, 36.8 mmol) in MeOH (30 mL) wasadded 10% Pd/C (300 mg) under N₂ at rt. The mixture was stirred at rtovernight under 50 psi of H₂. The reaction was filtered through Celiteand concentrated to give 6.5 g (92%) of the title compound as a whitesolid. [M+H] calc'd for C₁₂H₁₆O₂, 193; found 193.

Preparation 103C: 5,6-dimethyl-1,2,3,4-tetrahydronaphthalen-1-one

Preparation 103B (6.5 g, 33.9 mmol) was heated in PPA (5 mL) at 95° C.for 1.5 hr. The reaction was cooled, slowly quenched with sat NaHCO₃,and extracted with EtOAc (3×). Organics were dried (Na₂SO₄) andconcentrated. Purification by silica gel chromatography (PE:EtOAc=15:1)gave 4.0 g (68%) of the title compound as a brown solid. ¹H NMR (300MHz, CDCl₃): δ 2.11-2.19 (2H, m), 2.23 (3H, s), 2.36 (3H, s), 2.62 (2H,d, J=6.3 Hz), 2.91 (2H, t, J 6.3 Hz), 7.14 (1H, d, J=7.8 Hz), 7.87 (1H,d, J=7.8 Hz).

Preparation 103D:(5,6-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 49% overall yield from Preparation103C according to the procedure for Preparation 63A, with the exceptionthat the dehydration step ran for 10 min instead of overnight. [M+H]calc'd for C₁₃H₁₉N, 190; found 190.

Example 103:3-{[(5,6-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicacid

The title compound was prepared in 20% yield from Preparation 103D and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 1.72-1.78 (4H, m), 2.08 (3H,s), 2.20 (3H, s), 2.50-2.64 (2H, m), 3.04-3.07 (1H, m), 3.39-3.55 (2H,m), 6.93 (1H, d, J=7.8 Hz), 7.03 (1H, d, J=7.8 Hz), 7.56 (1H, d, J=5.1Hz), 7.83 (1H, d, J=5.4 Hz), 8.36 (1H, s). [M+H] calc'd for C₁₉H₂₂N₂O₂,311; Found, 311.

Preparation 104A:6-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (5.0 g, 30.8mmol) and 2-chloro-6-(trifluoromethyl)pyridine (5.87 g, 32.3 mmol) inACN (100 mL) was added potassium carbonate (6.39 g, 46.2 mmol), and thereaction was heated at 120° C. in a sealed vessel overnight. Thereaction was cooled, diluted with water (100 mL), and extracted withEtOAc (100 mL×3). Organics were dried (Na₂SO₄), and concentrated.Purification by silica gel chromatography (10%-80% EtOAc/hexanes) gave5.8 g (61%) of the title compound as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ 2.13-2.20 (2H, m), 2.67 (2H, t, J=6.2 Hz), 2.97 (2H, t, J=6.0Hz), 7.07-7.14 (2H, m), 7.45 (1H, d, J=7.4 Hz), 7.89 (1H, t, J=8.0 Hz),8.09 (1H, d, J=8.3 Hz). [M+H] calc'd for C₁₆H₁₂F₃NO₂, 308; found 308.

Preparation 104B:(6-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 30% yield from Preparation 104Aaccording to the general procedure for Preparation 63A, with theexception that the dehydration step reaction time was 1 hr. ¹H NMR (400MHz, CDCl₃): δ 1.75-1.93 (4H, m), 2.74-2.78 (2H, m), 2.85-2.94 (1H, m),2.96-3.03 (m, 2H), 6.89-6.99 (3H, m), 7.22 (1H, d, J=8.4 Hz), 7.36 (1H,d, J=7.4 Hz), 7.80 (1H, t, J=7.8 Hz). [M+H] calc'd for C₁₇H₁₇F₃N₂O, 323;found 323.

Example 104:3-{[(6-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid

The title compound was prepared in 15% yield from Preparation 104B and3-fluoroisonicotinic acid according to the procedure for the preparationof Example 3. ¹H NMR (400 MHz, DMSO-d₆): δ 1.67-1.88 (4H, m), 2.72-2.77(2H, m), 3.14-3.19 (1H, m), 3.45-3.51 (1H, m), 3.61-3.66 (1H, m),6.95-6.99 (2H, m), 7.23 (1H, d, J=8.4 Hz), 7.41 (1H, d, J=8.2 Hz),7.57-7.64 (2H, m), 7.83 (1H, d, J=4.7 Hz), 8.10 (1H, t, J=7.9 Hz), 8.38(1H, s). [M+H] Calc'd for C₂₃H₂₀F₃N₃O₃, 444; Found, 444.

II. Biological Evaluation

Example 1: In Vitro Enzyme Inhibition Assay

This assay determines the ability of a test compound to inhibit Jarid1A,Jarid1B, and JMJD2C demethylase activity. Baculovirus expressed Jarid1A(GenBank Accession #NM_001042603, AA1-1090) was purchased from BPSBioscience (Cat#50110). Baculovirus expressed Jarid1B (GenBank Accession#NM_006618, AA 2-751) was purchased from BPS Bioscience (Cat #50121) orcustom made by MolecularThroughput. Baculovirus-expressed JMJD2C(GenBank Accession #BC143571, AA 2-372) was purchased from BPSBioscience (Cat#50105).

Jarid1A Assay

The enzymatic assay of Jarid1A activity is based upon TimeResolved-Fluorescence Resonance Energy Transfer (TR-FRET) detection. Theability of test compounds to inhibit the activity of Jarid1A wasdetermined in 384-well plate format under the following reactionconditions: 1 nM Jarid1A, 300 nM H3K4me3-biotin labeled peptide (Anaspeccat #64357), 2 μM alpha-ketoglutaric acid in assay buffer of 50 mMHEPES, pH 7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-mono-or di-methylated histone H3 lysine 4 (H3K4me1-2)antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detectionbuffer (PerkinElmer) at a final concentration of 25 nM and 1 nM,respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K4me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO was addedto each well of plate, followed by the addition of 2 μl of 3 nM Jarid1Ato initiate the reaction. The reaction mixture was incubated at rt for30 min, and terminated by the addition of 6 μl of 5 mM EDTA in LANCEdetection buffer containing 50 nM Phycolink Streptavidin-allophycocyaninand 2 nM Europium-anti-H3K4me1-2 antibody. Plates were read byEnVisionMultilabel Reader in TR-FRET mode (excitation at 320 nm,emission at 615 nm and 665 nm) after 1 hr incubation at rt. A ratio wascalculated (665/615) for each well and fitted to determine inhibitionconstant (IC₅₀).

Jarid1B Assay

The ability of test compounds to inhibit the activity of Jarid1B wasdetermined in 384 well plate format under the following reactionconditions: 0.8 nM Jarid1B, 300 nM H3K4me3-biotin labeled peptide(Anaspec cat #64357), 2 μM alpha-ketoglutaric acid in assay buffer of 50mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-mono-or di-methylated histone H3 lysine 4 (H3K4me1-2)antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detectionbuffer (PerkinElmer) at a final concentration of 25 nM and 1 nM,respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K4me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO was addedto each well of the plate, followed by the addition of 2 μl of 2.4 nMJarid1B to initiate the reaction. The reaction mixture was incubated atrt for 30 min, and terminated by the addition of 6 μl of 5 mM EDTA inLANCE detection buffer containing 50 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K4me1-2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hrincubation at rt. A ratio was calculated (665/615) for each well andfitted to determine inhibition constant (IC₅₀).

JMJD2C Assay

The ability of test compounds to inhibit the activity of JMJD2C wasdetermined in 384-well plate format under the following reactionconditions: 0.3 nM JMJD2C, 300 nM H3K9me3-biotin labeled peptide(Anaspec cat #64360), 2 μM alpha-ketoglutaric acid in assay buffer of 50mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody(PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer(PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K9me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO wereadded to each well of the plate, followed by the addition of 2 μl of 0.9nM JMJD2C to initiate the reaction. The reaction mixture was incubatedat room temperature for 30 min, and terminated by the addition of 6 μlof 5 mM EDTA in LANCE detection buffer containing 100 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hrincubation at rt. A ratio was calculated (665/615) for each well andfitted to determine inhibition constant (IC₅₀).

An assay to determine the ability of test compounds to inhibit theactivity of JMJD2A was developed and disclosed in U.S. ProvisionalApplication 61/792,930 and is incorporated by reference herein.

The ability of the pyridine and pyridazine compounds disclosed herein toinhibit demethylase activity was quantified and the respective IC₅₀value was determined. Table 3 provides the IC₅₀ values of variouscompounds disclosed herein.

TABLE 3 Chemical Synthesis JARID1A JARID1B JMJD2C Example Name IC₅₀ (μM)IC₅₀ (μM) IC₅₀ (μM)  1 3-(benzylamino)pyridazine-4- A B A carboxylicacid  2 3-[(2-fluorobenzyl)amino] pyridine-4- A A A carboxylic acid  33-[(3-fluorobenzyl)amino] pyridine-4- A A A carboxylic acid  43-[(4-fluorobenzyl)amino] pyridine-4- A A A carboxylic acid  53-[(4-cyanobenzyl)amino] pyridine-4- A A A carboxylic acid  63-{[4-hydroxymethyl) A A A benzyl]amino}pyridine-4- carboxylic acid  73-[(4-methoxybenzyl)amino] pyridine-4- A A A carboxylic acid  83-{[4-(trifluoromethyl)benzyl]amino} A A A pyridine-4-carboxylic acid  93-[(biphenyl-4-ylmethyl) A B C amino]pyridine-4-carboxylic acid 103-[(4-chlorobenzyl)amino] pyridine-4- A A A carboxylic acid 113-{[4-(propan-2-yloxy)benzyl] A A B amino}pyridine-4-carboxylic acid 123-[(4-phenoxybenzyl)amino] pyridine-4- A A B carboxylic acid 133-({2-[(dimethylamino)methyl] A A A benzyl}amino)pyridine-4- carboxylicacid 14 3-[(3,4-dichlorobenzyl)amino] pyridine- A A A 4-carboxylic acid15 3-[(4-chloro-2-methylbenzyl) A A A amino]pyridine-4-carboxylic acid16 3-[(2,4-dimethyoxybenzyl)amino] A A B pyridine-4-carboxylic acid 173-[(2-hydroxybenzyl)amino] pyridine-4- A A A carboxylic acid 183-[(2,4-dichlorobenzyl)amino] pyridine- A A A 4-carboxylic acid 193-[(2-cyclopropylbenzyl)amino] A A A pyridine-4-carboxylic acid 203-[(4-chloro-2-methoxybenzyl) A A B amino]pyridine-4-carboxylic acid 213-[(4-chloro-2-hydroxybenzyl) A A A amino]pyridine-4-carboxylic acid 223-[(2-aminobenzyl)amino] pyridine-4- A A A carboxylic acid 233-[(4-bromobenzyl)amino] pyridine-4- A A A carboxylic acid 243-[(4-methylbenzyl)amino] pyridine-4- A A A carboxylic acid 253-[(4-cyclopropylbenzyl)amino] A A B pyridine-4-carboxylic acid 263-[(4-chloro-2-cyclopropylbenzyl) A A B amino]pyridine-4-carboxylic acid27 3-{[2-cyclopropyl-4-(trifluoro-methl) A A Bbenzyl]amino}pyridine-4-carboxylic acid 28 3-[(naphthalene-1-ylmethyl) AA A amino]pyridine-4-carboxylic acid 29 3-[(1H-indol-7-ylmethyl) A A Aamino]pyridine-4-carboxylic acid 30 3-[(2-cyclopropyl-3-methylbenzyl) AA A amino]pyridine-4-carboxylic acid 313-{[(4-cyclopropylpyridin-3-yl)-methyl] A A Aamino}pyridine-4-carboxylic acid 32 3-{[3-(trifluoromethyl)benzyl] A A Aamino}pyridine-4-carboxylic acid 33 3-[(2-phenoxybenzyl)amino]pyridine-4- A A B carboxylic acid 34 3-[(2-cyclopropyl-5-methylbenzyl) AA B amino]pyridine-4-carboxylic acid 35 3-{[3-(trifluoromethoxy) B B Bbenzyl]amino}pyridine-4-carboxylic acid 36 3-{[2-(phenylaminol)benzyl] AA B amino}pyridine-4-carboxylic acid 37 3-{[3-(cyclopropylmethoxy) B A Bbenzyl]amino}pyridine-4- carboxylic acid 38 3-[(1-benzofuran-3-ylmethyl)A A B amino]pyridine-4-carboxylic acid 39 3-{[(5-methylthiophen-2-yl) AA A methyl]amino}pyridine-4- carboxylic acid 403-{[(5-methylfuran-2-yl)methyl] A A A amino}pyridine-4-carboxylic acid41 3-[(1-benzofuran-2-ylmethyl)amino] A A A pyridine-4-carboxylic acid42 3-[(adamantan-1-ylmethyl) B B A amino]pyridine-4-carboxylic acid 433-[(2,3-dihydro-1-benzofuran-2- A A A ylmethyl)amino]pyridine-4-carboxylic acid 44 3-[(2,3-dihydro-1,4-benzodioxin-2- A A Aylmethyl)amino]pyridine-4- carboxylic acid 453-[(2,3-dihydro-1H-inden-1- A A A ylmethylbenzyl) amino]pyridine-4-carboxylic acid 46 3-[(1,2,3,4-tetrahydronaphthalen-1- A A B ylmethyl)amino]pyridine-4- carboxylic acid 473-{[(1S)-1,2,3,4-tetrahydro-naphthalen- A/B A/B B/B and 1-ylmethyl]amino} pyridine-4- 48 carboxylic acid;3-{[(1R)-1,2,3,4-tetrahydro-naphthalen- 1-yl methyl]amino} pyridine-4-carboxylic acid 49 3-{[(1-methyl-1,2,3,4-tetrahydro- B B Bnaphthalen-1-yl)methyl]amino}pyridine- 4-carboxylic acid 503-{[(7-fluoro-1,2,3,4-tetrahydro- — A Bnaphthalen-1-yl)methyl]amino}pyridine- 4-carboxylic acid 513-{[(7-fluoro-3,4-dihydronaphthalen- — — B 1-yl)methyl]amino}pyridine-4-carboxylic acid 52 3-{[(5,7-dimethyl-1,2,3,4-tetra- — — Chydronaphthalen-1-yl)methyl] amino}pyridine-4-carboxylic acid 533-{[(7-cyclopropyl-1,2,3,4-tetra-hydro- A A Bnaphthalen-1-yl)methyl]amino}pyridine- 4-carboxylic acid 543-{[(5-fluoro-1,2,3,4-tetrahydro- — — B naphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 55 3-{[(5-fluoro-1-hydroxy-1,2,3,4- — — Btetrahydronaphthalen-1-yl)methyl] amino}pyridine-4-carboxylic acid 563-({[(1S)-5-fluoro-1,2,3,4-tetrahydro- — — A/B andnaphthalen-1-yl]methyl}amino)pyridine- 57 4-carboxylic acid;3-({[(1R)-5-fluoro-1,2,3,4-tetrahydro- naphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 58 3-[(3,4-dihydro-2H-chromen-4- A A Aylmethyl) amino]pyridine-4- carboxylic acid 593-{[(4,4-dimethyl-1,2,3,4-tetrahydro- — — Bnaphthalen-1-yl)methyl]amino}pyridine- 4-carboxylic acid 603-{[(6-methoxy-1,2,3,4- A A B tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 613-({[(1S)-6-methoxy-1,2,3,4-tetrahydro- — — B/B andnaphthalen-1-yl]methyl} 62 amino)pyridine-4-carboxylic acid;3-({[(1R)-6-methoxy-1,2,3,4-tetrahydro- naphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 633-{[(6-methyl-3,4-dihydro-2H-chromen- A A B 4-yl)methyl]amino}pyridine-4- carboxylic acid 643-({[(6-(propan-2-yloxy)-1,2,3,4- — — Btetrahydronaphthalen-1-yl]methyl} amino)pyridine-4-carboxylic acid 653-{[(7-fluoro-3,4-dihydro-2H-chromen- — — A 4-yl)methyl]amino}pyridine-4- carboxylic acid 663-{[(7-chloro-3,4-dihydro-2H-chromen- — — B 4-yl)methyl]amino}pyridine-4- carboxylic acid 673-{[(6-chloro-1-hydroxy-1,2,3,4- — — B tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 68 3-{[(6-chloro-1,2,3,4- — — Btetrahydronaphthalen-1-yl)methyl] amino}pyridine-4-carboxylic acid 693-{[(7-phenyl-3,4-dihydro-2H-chromen- — — B4-yl)methyl]amino}pyridine-4- carboxylic acid 703-{[(7-fluoro-3,4-dihydro-2H-chromen- — — B 4-yl)methyl]amino}pyridine-4- carboxylic acid 713-{[(8-fluoro-3,4-dihydro-2H-chromen- — — A 4-yl)methyl]amino}pyridine-4- carboxylic acid 72 3-{[(7-chloro-1,2,3,4- — — Btetrahydronaphthalen-1-yl)methyl] amino}pyridine-4-carboxylic acid 733-{[(7-phenyl-1,2,3,4- — — B tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 74 3-{[(5-methoxy-1,2,3,4- — — Btetrahydronaphthalen-1-yl)methyl] amino}pyridine-4-carboxylic acid 753-{[(7-cyclopropyl-3,4-dihydro-2H- — — Bchromen-4-yl)methyl]amino}pyridine-4- carboxylic acid 763-({[(5-(cyclopropylmethoxy)-1,2,3,4- — — Ctetra-hydronaphthalen-1-yl]methyl} amino)pyridine-4-carboxylic acid 773-{[(5-phenoxy-1,2,3,4- — — C tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 78 3-[(3,4-dihydro-2H-thiochromen-4-yl-— — B methyl)amino]pyridine-4- carboxylic acid 793-({[(6-(3,3,3-trifluoropropoxy)-1,2,3,4- — — Btetrahydronaphthalen-1-yl]methyl} amino)pyridine-4-carboxylic acid 803-{[(5-phenoxy-1,2,3,4- — — B tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 813-({[(6-(cyclopropylmethoxy)-1,2,3,4- — — Btetrahydronaphthalen-1-yl]methyl} amino) pyridine-4-carboxylic acid 823{[(1-methyl-1,2,3,4-tetrahydroquinolin- — — B 4-yl)methyl]amino}pyridine-4- carboxylic acid 833-({[(4R)-7-phenyl-3,4-dihydro-2H- — — B/B andchromen-4-yl]methyl}amino)pyridine-4- 84 carboxylic acid;3-({[(4S)-7-phenyl-3,4-dihydro-2H- chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid 85 3-({[(4S)-7-(3-fluorophenyl)-3,4- — — B/C anddihydro-2H-chromen-4-yl]methyl} 86 amino)pyridine-4-carboxylic acid;3-({[(4R)-7-(3-fluorophenyl)-3,4- dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid 87 3-({[(4S)-7-cyclopropyl-3,4-dihydro-— — A/B and 2H-chromen-4-yl]methyl}amino) 88 pyridine-4-carboxylic acid;3-({[(4R)-7-cyclopropyl-3,4-dihydro- 2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid 89 3-({[6-(2-phenylethoxy)-1,2,3,4- — — Btetrahydro-naphthalen-1-yl]methyl} amino)pyridine-4-carboxylic acid 903-({[6-(2,2,2-trifluoroethoxy)-1,2,3,4- — — Btetrahydronaphthalen-1-yl]methyl} amino) pyridine-4-carboxylic acid 913-({[7-(2-cyclopropylethyl)-3,4-dihydro- — — B 2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid 92 3-({[6-(trifluoromethoxy)-1,2,3,4- —— C tetrahydronaphthalen-1-yl]methyl} amino)pyridine-4-carboxylic acid93 3-({[(4S)-7-(4-fluorophenyl)-3,4- — — B/C anddihydro-2H-chromen-4-yl]methyl} 94 amino)pyridine-4-carboxylic acid;3-({[(4R)-7-(4-fluorophenyl)-3,4- dihydro-2H-chromen-4-yl]methyl}amino)pyridine-4-carboxylic acid 95 3-({[(4S)-7-(2-fluorophenyl)-3,4- —— B/C and dihydro-2H-chromen-4-yl] methyl} 96amino)pyridine-4-carboxylic acid; 3-({[(4R)-7-(2-fluorophenyl)-3,4-dihydro-2H-chromen-4-yl] methyl} amino)pyridine-4-carboxylic acid 973-({[(1S)-6-(2-cyclopropylethoxy)- — — B/C and1,2,3,4-tetrahydronaphthalen-1-yl] 98 methyl}amino)pyridine-4-carboxylic acid; 3-({[(1R)-6-(2-cyclopropylethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl] methyl}amino)pyridine-4- carboxylicacid 99 3-({[(1S)-6-(3,3,3-trifluoro-propoxy)- — — B/B and1,2,3,4-tetrahydro-naphthalen-1-yl] 100  methyl}amino) pyridine-4-carboxylic acid; 3-({[(1R)-6-(3,3,3-trifluoro-propoxy)-1,2,3,4-tetra-hydronaphthalen-1-yl] methyl} amino)pyridine-4- carboxylicacid 101  3-({[6-(3,3,3-trifluoropropoxy)-1,2,3,4- — — Btetrahydronaphthalen-1-yl] methyl} amino)pyridazine-4-carboxylic acid102  3-{[(5-fluoro-6-methoxy-1,2,3,4- — — Btetrahydro-naphthalen-1-yl)methyl] amino}pyridine-4-carboxylic acid 103 3-{[(5,6-dimethyl-1,2,3,4-tetrahydro- — — B naphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 104 3-{[(6-{[6-(trifluoromethyl)pyridin-2- — — Byl]oxy}-1,2,3,4-tetrahydro-naphthalen- 1-yl)methyl] amino}pyridine-4-carboxylic acid Note: Biochemical assay IC₅₀ data are designated withinthe following ranges: A: ≦0.10 μM; B: >0.10 μM to ≦1.0 μM; C: >1.0 μM to≦10 μM; D: >10 μM

Example 2: In Vitro Cell-Based Assay

The primary cellular assay for JMJD2C inhibition is an assay whichmeasures cellular proliferation via Bromodeoxyuridine (BrdU)incorporation after 168 hours of compound incubation. Cell lines testedinclude the JMJD2C gene amplified cell line KYSE-150. This is aquantitative ELISA assay measuring DNA incorporation of BrdU duringS-phase as a direct readout of cellular proliferation.

Assay Principle: This is a colorimetric immunoassay for thequantification of cell proliferation. Cells treated for 168 hr with testcompounds are assayed for their ability to go through S-phase as ameasure of their proliferative potential.

Assay Method: The human KYSE-150 (SMAD4 mut, TP53 mut) esophagealcarcinoma cell line was seeded at 2,000 cells/well on a 96-well tissueculture treated plate. After an overnight incubation, cells were treatedwith compound in an 11-point dilution series with final concentrationsranging from 100 μM to 2 nM. Cells were then incubated in the presenceof compound for 168 hr. After compound incubation the cells were assayedusing a BrdU Cell Proliferation ELISA (Roche). The cells were firstincubated with BrdU labeling reagent for 2 hours. After 2 hours, theBrdU incorporated cells were fixed and denatured, probed with ananti-BrdU-Peroxidase antibody for 1.5 hr and washed. Finally, atetramethylbenzidine peroxidase substrate was added to each well for 15min followed by a H₂SO₄ stop solution. The plate was read at 450 nm, andthe raw optical density data was transferred into XLFit (IDBS) for IC₅₀calculation using the formula:

fit=(D+((Vmax*(x̂n))/((x̂n)+(Km̂n))))

A fluorometric immunoassay for the quantification of tri-methyl H3K4extracted from cells treated with test compound and used as a measure ofthe cellular inhibition of KDM5A/B was developed and disclosed in U.S.Provisional Application 61/792,930 and is incorporated by referenceherein.

Table 4 provides the cellular IC₅₀ values of various compounds disclosedherein.

TABLE 4 Example Cellular IC₅₀ (μM)  5 D  5A D  8A D 10 D 10A D 14 D 14AC 15 D 16 D 17 D 18 D 19 D 23 D 25 D 25A D 26 D 26A C 28 D 30 D 30A D32A D 38 D 39 D 40 D 41 D 42 D 42A C 45 D 46 C 47/48 C/D 49 D 50 C 51 D52 B 53 C 54 D 56/57 C/D 58 D 59 D 60 C 61/62 B/D 63 D 64 C 66 D 67 C 69C 72 C 75 C 79 C 80 A 81 C 82 D 83/84 B/— 85/86 B/— 87/88 C/— 89 B 90 C91 B 99/100 C/— Biochemical assay IC₅₀ data are designated within thefollowing ranges: A: ≦0.10 μM; B: >0.10 μM to ≦1.0 μM; C: >1.0 μM to ≦10μM; D: >10 μM

Example 3: In Vivo Xenograph Study

Time release pellets containing 0.72 mg 17-13 Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Cells are spun down andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells are subcutaneously injected (100 μL/animal) on theright flank 2-3 days post pellet implantation and tumor volume(length×width²/2) is monitored bi-weekly. When tumors reach an averagevolume of ˜200 mm³ animals are randomized and treatment is started.Animals are treated with vehicle or compound daily for 4 weeks. Tumorvolume and body weight are monitored bi-weekly throughout the study. Atthe conclusion of the treatment period, plasma and tumor samples aretaken for pharmacokinetic and pharmacodynamic analyses, respectively.

III. Preparation of Pharmaceutical Dosage Forms

Example 1: Oral Tablet

A tablet is prepared by mixing 48% by weigh of a compound of Formula (I)or a pharmaceutically acceptable salt thereof, 45% by weight ofmicrocrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate.

Tablets are prepared by direct compression. The total weight of thecompressed tablets is maintained at 250-500 mg.

We claim:
 1. A compound of Formula (XI), or a pharmaceuticallyacceptable salt thereof,

wherein: Q is carboxylic acid; and G is —X—Y, wherein X is —C₁ alkylene;Y is tetralinyl, optionally substituted with at least one halogen,hydroxyl, alkyl, carbocyclylalkyl, carbocyclylalkoxy, alkoxy, aryloxy,arylalkoxy, haloalkyloxy, or pyridinyl.
 2. The compound of claim 1,wherein Y is substituted with halogen.
 3. The compound of claim 1,wherein Y is substituted with at least one methyl.
 4. The compound ofclaim 1, wherein Y is substituted with halogen selected from chloro orfluoro.
 5. The compound of claim 5, wherein Y is further substitutedwith hydroxyl.
 6. The compound of claim 1, wherein Y is substituted withphenyl.
 7. The compound of claim 1, wherein Y is substituted witharyloxy or arylalkoxy selected from phenoxy, or phenylethoxy.
 8. Thecompound of claim 1, wherein Y is substituted with trifluoromethoxy, ortrifluoroethoxy.
 9. The compound of claim 1, wherein Y is substitutedwith cyclopropyl, cyclopropylmethyl, or cyclopropylethyl.
 10. Thecompound of claim 1, wherein Y is substituted with trifluoropropynyl orcyclopropylethynyl.
 11. The compound of claim 1, wherein Y issubstituted with pyridinyl.
 12. A pharmaceutical composition comprisingthe compound of claim 1 and at least one pharmaceutically acceptablecarrier.
 13. A method of treating cancer in a subject in need thereofcomprising administering to the subject the pharmaceutical compositionof claim
 12. 14. A method of inhibiting a histone demethylase enzymecomprising contacting the histone demethylase enzyme with the compoundof claim 1.